EP4103692A1 - Novel tdzd analogs as agents that delay, prevent, or reverse age-associated diseases; and as anti-cancer and antileukemic agents - Google Patents
Novel tdzd analogs as agents that delay, prevent, or reverse age-associated diseases; and as anti-cancer and antileukemic agentsInfo
- Publication number
- EP4103692A1 EP4103692A1 EP21754449.3A EP21754449A EP4103692A1 EP 4103692 A1 EP4103692 A1 EP 4103692A1 EP 21754449 A EP21754449 A EP 21754449A EP 4103692 A1 EP4103692 A1 EP 4103692A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- compound
- cancer
- haloalkyl
- och
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 91
- 239000003795 chemical substances by application Substances 0.000 title claims description 40
- 239000002246 antineoplastic agent Substances 0.000 title claims description 30
- 201000010099 disease Diseases 0.000 title abstract description 28
- 230000001093 anti-cancer Effects 0.000 title description 6
- 239000000063 antileukemic agent Substances 0.000 title description 4
- 230000002441 reversible effect Effects 0.000 title description 2
- 238000011282 treatment Methods 0.000 claims abstract description 55
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 48
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims abstract description 14
- 208000032839 leukemia Diseases 0.000 claims abstract description 14
- 230000002489 hematologic effect Effects 0.000 claims abstract description 12
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 11
- 208000001076 sarcopenia Diseases 0.000 claims abstract description 11
- 206010048327 Supranuclear palsy Diseases 0.000 claims abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 9
- 206010025323 Lymphomas Diseases 0.000 claims abstract description 9
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 9
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 9
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 9
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 9
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 9
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 9
- 201000001441 melanoma Diseases 0.000 claims abstract description 9
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 9
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 9
- 208000003174 Brain Neoplasms Diseases 0.000 claims abstract description 7
- 201000009030 Carcinoma Diseases 0.000 claims abstract description 7
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 7
- 206010014733 Endometrial cancer Diseases 0.000 claims abstract description 7
- 206010014759 Endometrial neoplasm Diseases 0.000 claims abstract description 7
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims abstract description 7
- 206010018338 Glioma Diseases 0.000 claims abstract description 7
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims abstract description 7
- 206010039491 Sarcoma Diseases 0.000 claims abstract description 7
- 208000000453 Skin Neoplasms Diseases 0.000 claims abstract description 7
- 208000024313 Testicular Neoplasms Diseases 0.000 claims abstract description 7
- 206010057644 Testis cancer Diseases 0.000 claims abstract description 7
- 208000024770 Thyroid neoplasm Diseases 0.000 claims abstract description 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 7
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 7
- 201000000050 myeloid neoplasm Diseases 0.000 claims abstract description 7
- 208000010626 plasma cell neoplasm Diseases 0.000 claims abstract description 7
- 201000000849 skin cancer Diseases 0.000 claims abstract description 7
- 201000003120 testicular cancer Diseases 0.000 claims abstract description 7
- 201000002510 thyroid cancer Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 296
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 229
- 229910052739 hydrogen Inorganic materials 0.000 claims description 229
- 239000001257 hydrogen Substances 0.000 claims description 227
- -1 benzoxadiazolyl Chemical group 0.000 claims description 204
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 181
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 178
- 125000003282 alkyl amino group Chemical group 0.000 claims description 168
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 163
- 229910052736 halogen Inorganic materials 0.000 claims description 145
- 150000002367 halogens Chemical class 0.000 claims description 145
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 137
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 137
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 127
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 126
- 125000003118 aryl group Chemical group 0.000 claims description 125
- 238000000034 method Methods 0.000 claims description 119
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 109
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 107
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 105
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 102
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 101
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 88
- 125000001072 heteroaryl group Chemical group 0.000 claims description 87
- 150000003839 salts Chemical class 0.000 claims description 79
- 239000000203 mixture Substances 0.000 claims description 68
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 67
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 65
- 208000035475 disorder Diseases 0.000 claims description 63
- 125000001188 haloalkyl group Chemical group 0.000 claims description 60
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 49
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 46
- 230000004663 cell proliferation Effects 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 41
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 208000012902 Nervous system disease Diseases 0.000 claims description 36
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- 201000011510 cancer Diseases 0.000 claims description 25
- 125000004001 thioalkyl group Chemical group 0.000 claims description 25
- 150000001356 alkyl thiols Chemical class 0.000 claims description 24
- 229940127089 cytotoxic agent Drugs 0.000 claims description 24
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 24
- 125000004971 nitroalkyl group Chemical group 0.000 claims description 24
- 208000024827 Alzheimer disease Diseases 0.000 claims description 19
- 241000124008 Mammalia Species 0.000 claims description 19
- 239000003937 drug carrier Substances 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 16
- 239000003112 inhibitor Substances 0.000 claims description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 13
- 150000007942 carboxylates Chemical group 0.000 claims description 11
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
- 239000002256 antimetabolite Substances 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 229940121849 Mitotic inhibitor Drugs 0.000 claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003972 antineoplastic antibiotic Substances 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 229940124302 mTOR inhibitor Drugs 0.000 claims description 4
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 3
- 108010006654 Bleomycin Proteins 0.000 claims description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 3
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 3
- 230000001078 anti-cholinergic effect Effects 0.000 claims description 3
- 239000000935 antidepressant agent Substances 0.000 claims description 3
- 229940005513 antidepressants Drugs 0.000 claims description 3
- 239000000164 antipsychotic agent Substances 0.000 claims description 3
- 229960001561 bleomycin Drugs 0.000 claims description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 3
- 229960002092 busulfan Drugs 0.000 claims description 3
- 229960004117 capecitabine Drugs 0.000 claims description 3
- 229960004562 carboplatin Drugs 0.000 claims description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
- 229960004630 chlorambucil Drugs 0.000 claims description 3
- 229960004316 cisplatin Drugs 0.000 claims description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
- 229960003668 docetaxel Drugs 0.000 claims description 3
- 229960001904 epirubicin Drugs 0.000 claims description 3
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 3
- 229960000390 fludarabine Drugs 0.000 claims description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 3
- 229960005277 gemcitabine Drugs 0.000 claims description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 3
- 229960001101 ifosfamide Drugs 0.000 claims description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 3
- 229960004768 irinotecan Drugs 0.000 claims description 3
- 229960001924 melphalan Drugs 0.000 claims description 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- 229960004857 mitomycin Drugs 0.000 claims description 3
- 229960001156 mitoxantrone Drugs 0.000 claims description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 3
- 229960003087 tioguanine Drugs 0.000 claims description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 3
- 229960000303 topotecan Drugs 0.000 claims description 3
- 229960003048 vinblastine Drugs 0.000 claims description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- 229960004528 vincristine Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 claims description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 2
- 229940099362 Catechol O methyltransferase inhibitor Drugs 0.000 claims description 2
- 229940122041 Cholinesterase inhibitor Drugs 0.000 claims description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- 108010092160 Dactinomycin Proteins 0.000 claims description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 229930192392 Mitomycin Natural products 0.000 claims description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 claims description 2
- 108010062431 Monoamine oxidase Proteins 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 2
- 230000001430 anti-depressive effect Effects 0.000 claims description 2
- 229960002707 bendamustine Drugs 0.000 claims description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 claims description 2
- 229960001573 cabazitaxel Drugs 0.000 claims description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 2
- 229960004205 carbidopa Drugs 0.000 claims description 2
- 229960005243 carmustine Drugs 0.000 claims description 2
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 claims description 2
- 201000007455 central nervous system cancer Diseases 0.000 claims description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 2
- 229960002436 cladribine Drugs 0.000 claims description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 claims description 2
- 229960000928 clofarabine Drugs 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 229960004397 cyclophosphamide Drugs 0.000 claims description 2
- 229960000684 cytarabine Drugs 0.000 claims description 2
- 229960003901 dacarbazine Drugs 0.000 claims description 2
- 229960000640 dactinomycin Drugs 0.000 claims description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 2
- 229960000975 daunorubicin Drugs 0.000 claims description 2
- 229960003603 decitabine Drugs 0.000 claims description 2
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims description 2
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 claims description 2
- 229950009041 edaravone Drugs 0.000 claims description 2
- 229960005167 everolimus Drugs 0.000 claims description 2
- 229960000961 floxuridine Drugs 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 229960000908 idarubicin Drugs 0.000 claims description 2
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 2
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 claims description 2
- 229960002014 ixabepilone Drugs 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 229960004502 levodopa Drugs 0.000 claims description 2
- 229960002247 lomustine Drugs 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004961 mechlorethamine Drugs 0.000 claims description 2
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims description 2
- 229960004640 memantine Drugs 0.000 claims description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 2
- 229960001428 mercaptopurine Drugs 0.000 claims description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 claims description 2
- 229960000801 nelarabine Drugs 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 2
- 229960001756 oxaliplatin Drugs 0.000 claims description 2
- 229960005079 pemetrexed Drugs 0.000 claims description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 2
- 229960002340 pentostatin Drugs 0.000 claims description 2
- 229960003171 plicamycin Drugs 0.000 claims description 2
- 229960000214 pralatrexate Drugs 0.000 claims description 2
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 claims description 2
- 229940072169 rilutek Drugs 0.000 claims description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 claims description 2
- 229950009213 rubitecan Drugs 0.000 claims description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims description 2
- 229960001052 streptozocin Drugs 0.000 claims description 2
- 229960004964 temozolomide Drugs 0.000 claims description 2
- 229960000235 temsirolimus Drugs 0.000 claims description 2
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 2
- 229960001278 teniposide Drugs 0.000 claims description 2
- 229960001196 thiotepa Drugs 0.000 claims description 2
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 2
- 229960000653 valrubicin Drugs 0.000 claims description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 2
- 229960002066 vinorelbine Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims 1
- 229960003805 amantadine Drugs 0.000 claims 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical group [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 claims 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 claims 1
- 229960003120 clonazepam Drugs 0.000 claims 1
- 238000012377 drug delivery Methods 0.000 claims 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 claims 1
- 229960004002 levetiracetam Drugs 0.000 claims 1
- 239000004050 mood stabilizer Substances 0.000 claims 1
- 239000002105 nanoparticle Substances 0.000 claims 1
- 229960005333 tetrabenazine Drugs 0.000 claims 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims 1
- 208000015122 neurodegenerative disease Diseases 0.000 abstract description 18
- 230000004770 neurodegeneration Effects 0.000 abstract description 14
- 230000000670 limiting effect Effects 0.000 abstract description 6
- 206010005003 Bladder cancer Diseases 0.000 abstract description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 abstract description 5
- 201000005112 urinary bladder cancer Diseases 0.000 abstract description 5
- 206010012289 Dementia Diseases 0.000 abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 136
- 239000000460 chlorine Substances 0.000 description 135
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 132
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 67
- 125000000217 alkyl group Chemical group 0.000 description 66
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 61
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 48
- 125000004432 carbon atom Chemical group C* 0.000 description 39
- 125000001424 substituent group Chemical group 0.000 description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
- 239000003814 drug Substances 0.000 description 35
- UXHCYSLUHBOEGI-UHFFFAOYSA-N 1-(4-bromophenyl)imino-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[3,4-a]pyridazin-3-one Chemical class C1=CC(Br)=CC=C1N=C1N2CCCCN2C(=O)S1 UXHCYSLUHBOEGI-UHFFFAOYSA-N 0.000 description 34
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 30
- 125000005842 heteroatom Chemical group 0.000 description 29
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 28
- 125000000392 cycloalkenyl group Chemical group 0.000 description 24
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 24
- 229910052799 carbon Inorganic materials 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 125000003342 alkenyl group Chemical group 0.000 description 22
- 238000004519 manufacturing process Methods 0.000 description 22
- 150000004820 halides Chemical class 0.000 description 21
- 229910002092 carbon dioxide Inorganic materials 0.000 description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 19
- 125000000304 alkynyl group Chemical group 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 17
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 17
- 239000001301 oxygen Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 229910052717 sulfur Inorganic materials 0.000 description 17
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 description 16
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 16
- 239000011593 sulfur Substances 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 description 14
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 14
- 125000001931 aliphatic group Chemical group 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- BUQLXKSONWUQAC-UHFFFAOYSA-N Parthenolide Natural products CC1C2OC(=O)C(=C)C2CCC(=C/CCC1(C)O)C BUQLXKSONWUQAC-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- KTEXNACQROZXEV-PVLRGYAZSA-N parthenolide Chemical compound C1CC(/C)=C/CC[C@@]2(C)O[C@@H]2[C@H]2OC(=O)C(=C)[C@@H]21 KTEXNACQROZXEV-PVLRGYAZSA-N 0.000 description 13
- 229940069510 parthenolide Drugs 0.000 description 13
- 150000003254 radicals Chemical class 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
- 229940002612 prodrug Drugs 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 150000003573 thiols Chemical class 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- BAURYGOYSLZFPX-ZVSUPFEUSA-N melampomagnolide b Chemical compound C1C\C=C(CO)/CC[C@H]2C(=C)C(=O)O[C@@H]2[C@H]2O[C@@]21C BAURYGOYSLZFPX-ZVSUPFEUSA-N 0.000 description 10
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 9
- BAURYGOYSLZFPX-UHFFFAOYSA-N Melampomagnolide B Natural products C1CC=C(CO)CCC2C(=C)C(=O)OC2C2OC21C BAURYGOYSLZFPX-UHFFFAOYSA-N 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 239000000969 carrier Substances 0.000 description 9
- BAURYGOYSLZFPX-ABHRYQDASA-N melampomagnolide B Natural products C[C@]12CCC=C(/CO)CC[C@@H]3[C@H](OC(=O)C3=C)[C@@H]1O2 BAURYGOYSLZFPX-ABHRYQDASA-N 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000001183 hydrocarbyl group Chemical group 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 229960001138 acetylsalicylic acid Drugs 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 229910052698 phosphorus Inorganic materials 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 150000001540 azides Chemical class 0.000 description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 150000002894 organic compounds Chemical class 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 230000004845 protein aggregation Effects 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000032683 aging Effects 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 238000010174 APPSwe Methods 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 229940124599 anti-inflammatory drug Drugs 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 230000036515 potency Effects 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 125000006239 protecting group Chemical class 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 150000003852 triazoles Chemical class 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical class [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229910004749 OS(O)2 Inorganic materials 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000004721 Polyphenylene oxide Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 230000008484 agonism Effects 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 230000000719 anti-leukaemic effect Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000002540 isothiocyanates Chemical class 0.000 description 3
- 125000000468 ketone group Chemical group 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical compound NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000008520 organization Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical class [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229920000570 polyether Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000002577 pseudohalo group Chemical group 0.000 description 3
- 229930009674 sesquiterpene lactone Natural products 0.000 description 3
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 125000005415 substituted alkoxy group Chemical group 0.000 description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- VOXBZHOHGGBLCQ-UHFFFAOYSA-N 2-amino-3,7-dihydropurine-6-thione;hydrate Chemical compound O.N1C(N)=NC(=S)C2=C1N=CN2.N1C(N)=NC(=S)C2=C1N=CN2 VOXBZHOHGGBLCQ-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 244000192528 Chrysanthemum parthenium Species 0.000 description 2
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 241000270322 Lepidosauria Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 102000038427 NEDD8-activating enzyme E1 Human genes 0.000 description 2
- 108091007790 NEDD8-activating enzyme E1 Proteins 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 241000244206 Nematoda Species 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 2
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 102000004389 Ribonucleoproteins Human genes 0.000 description 2
- 108010081734 Ribonucleoproteins Proteins 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 102000002689 Toll-like receptor Human genes 0.000 description 2
- 108020000411 Toll-like receptor Proteins 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000005431 alkyl carboxamide group Chemical group 0.000 description 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- 125000004069 aziridinyl group Chemical group 0.000 description 2
- 125000005873 benzo[d]thiazolyl group Chemical group 0.000 description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 150000005347 biaryls Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 125000005432 dialkylcarboxamide group Chemical group 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 235000008384 feverfew Nutrition 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000001030 gas--liquid chromatography Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 230000006951 hyperphosphorylation Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 229940047122 interleukins Drugs 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229940029985 mineral supplement Drugs 0.000 description 2
- 235000020786 mineral supplement Nutrition 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000005561 phenanthryl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229920001281 polyalkylene Polymers 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 125000004941 pyridazin-5-yl group Chemical group N1=NC=CC(=C1)* 0.000 description 2
- 125000004942 pyridazin-6-yl group Chemical group N1=NC=CC=C1* 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- OMJKFYKNWZZKTK-POHAHGRESA-N (5z)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1/N=CN=C1C(N)=O OMJKFYKNWZZKTK-POHAHGRESA-N 0.000 description 1
- 125000006686 (C1-C24) alkyl group Chemical group 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- 125000006694 (C2-C10) heterocyclyl group Chemical group 0.000 description 1
- 125000006695 (C2-C11) heterocyclyl group Chemical group 0.000 description 1
- 125000006696 (C2-C18) heterocyclyl group Chemical group 0.000 description 1
- 125000006687 (C2-C3) heterocyclyl group Chemical group 0.000 description 1
- 125000006688 (C2-C4) heterocyclyl group Chemical group 0.000 description 1
- 125000006689 (C2-C5) heterocyclyl group Chemical group 0.000 description 1
- 125000006690 (C2-C6) heterocyclyl group Chemical group 0.000 description 1
- 125000006691 (C2-C7) heterocyclyl group Chemical group 0.000 description 1
- 125000006692 (C2-C8) heterocyclyl group Chemical group 0.000 description 1
- 125000006693 (C2-C9) heterocyclyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZGNLFUXWZJGETL-YUSKDDKASA-N (Z)-[(2S)-2-amino-2-carboxyethyl]-hydroxyimino-oxidoazanium Chemical compound N[C@@H](C\[N+]([O-])=N\O)C(O)=O ZGNLFUXWZJGETL-YUSKDDKASA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- HTJMXYRLEDBSLT-UHFFFAOYSA-N 1,2,4,5-tetrazine Chemical compound C1=NN=CN=N1 HTJMXYRLEDBSLT-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- UDGKZGLPXCRRAM-UHFFFAOYSA-N 1,2,5-thiadiazole Chemical compound C=1C=NSN=1 UDGKZGLPXCRRAM-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- QHOINBKBMJLHPY-UHFFFAOYSA-N 2-chloroethyl formate Chemical compound ClCCOC=O QHOINBKBMJLHPY-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- 102100033639 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 230000007082 Aβ accumulation Effects 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- 102000001805 Bromodomains Human genes 0.000 description 1
- 108050009021 Bromodomains Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- MLFKVJCWGUZWNV-UHFFFAOYSA-N L-alanosine Natural products OC(=O)C(N)CN(O)N=O MLFKVJCWGUZWNV-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000003293 Magnolia grandiflora Species 0.000 description 1
- 235000008512 Magnolia grandiflora Nutrition 0.000 description 1
- DUEDDXAOCLBLLA-UHFFFAOYSA-N Melampolide Natural products CC(=O)OCC=C(/C)C(=O)OC1CC(=C/CCC(=CC2OC(=O)C(=C)C12)C)C=O DUEDDXAOCLBLLA-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101710115937 Microtubule-associated protein tau Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IGFHQQFPSIBGKE-UHFFFAOYSA-N Nonylphenol Natural products CCCCCCCCCC1=CC=C(O)C=C1 IGFHQQFPSIBGKE-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920001774 Perfluoroether Chemical group 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 238000004617 QSAR study Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 241000255588 Tephritidae Species 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229950005033 alanosine Drugs 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940124346 antiarthritic agent Drugs 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000002579 antinauseant Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000002617 bone density conservation agent Substances 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- QTAOMKOIBXZKND-PPHPATTJSA-N carbidopa Chemical compound O.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 QTAOMKOIBXZKND-PPHPATTJSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000000718 cholinopositive effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- HRYLQFBHBWLLLL-AHNJNIBGSA-N costunolide Chemical compound C1CC(/C)=C/CC\C(C)=C\[C@H]2OC(=O)C(=C)[C@@H]21 HRYLQFBHBWLLLL-AHNJNIBGSA-N 0.000 description 1
- 229940037530 cough and cold preparations Drugs 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000005959 diazepanyl group Chemical group 0.000 description 1
- 125000004915 dibutylamino group Chemical group C(CCC)N(CCCC)* 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- YZQRAQOSAPWELU-UHFFFAOYSA-O elliptinium Chemical compound C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 YZQRAQOSAPWELU-UHFFFAOYSA-O 0.000 description 1
- 229950007539 elliptinium Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229940005494 general anesthetics Drugs 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- XMBWDFGMSWQBCA-NJFSPNSNSA-N iodane Chemical compound [129IH] XMBWDFGMSWQBCA-NJFSPNSNSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 125000002463 lignoceryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QTZUMCMRRPENJM-LJQANCHMSA-N n-[(1s)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]-2-(oxan-4-ylamino)-6,8-dihydro-5h-pyrido[3,4-d]pyrimidine-7-carboxamide Chemical compound N([C@H](CO)C=1C=C(Cl)C(F)=CC=1)C(=O)N(CC1=N2)CCC1=CN=C2NC1CCOCC1 QTZUMCMRRPENJM-LJQANCHMSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 239000002698 neuron blocking agent Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000006959 non-competitive inhibition Effects 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SNQQPOLDUKLAAF-UHFFFAOYSA-N nonylphenol Chemical compound CCCCCCCCCC1=CC=CC=C1O SNQQPOLDUKLAAF-UHFFFAOYSA-N 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004175 parthenolide derivatives Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229940109328 photofrin Drugs 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001748 polybutylene Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 125000004585 polycyclic heterocycle group Chemical group 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000014483 powder concentrate Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000006318 protein oxidation Effects 0.000 description 1
- 230000004844 protein turnover Effects 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229930004725 sesquiterpene Natural products 0.000 description 1
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000013024 troubleshooting Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Definitions
- TTZD 2,4-disubstituted thiadiazolidinone
- This disclosure provides compounds having a structure represented by a formula: wherein m is 0, 1, 2, or 3; wh 0 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)OC(O)(C1-C10 alkyl), ⁇ (C1-C10 alkyl)NHC(
- This disclosure also provides compounds having a structure represented by a formula: wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)OC(O)(C1-C10 alkyl), ⁇ (C1
- R1 refers to H or different straight or branched chain hydrocarbyl groups or substituted hydrocarbyl with carbon numbers ranging from 0 to 10; or alkyl halides; or alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thiol or diverse hetero-aromatic or other aromatic ring.
- Halides refers to F, Cl, Br, or I (atoms of fluorine, chlorine, bromine or iodine).
- R2 refers to: where Y refers to only H or F or Cl or Br or I; or R 2 refers to aromatic or hetero-aromatic ring systems; 1-naphthyl or 2-napthyl group; different simple and substituted 2/3-furyl; 2 or 3 or 4 or 5 or 6 or 7-benzofuryl; 2 or 4 or 5-oxazolyl; 3 or 4 or 5-isoxazolyl; 4 or 5-oxadiazolyl, 2 or 4 or 5 or 6 or 7-benzoxazolyl; 4 or 5 or 6 or 7-benzoxadiazolyl; 2 or 3-pyrrolyl; 3 or 4 or 5-pyrazolyl; 2 or 4 or 5-imidazolyl; 2 or 3 or 4 or 5 or 6 or 7-quinolyl; 2 or 4 or 5 or 6 or 7-quinazolyl; 3 or 4 or 5 or 6
- TTZD thiadiazolidinone
- FIG.1 The thiadiazolidinone (TDZD) ring system 1 (FIG.1) possesses several interesting pharmacological properties, including inhibition of acetylcholinesterase activity (Martinez et al. (2000) Eur J Med Chem.35(10): 913-922), inhibition of glycogen synthase kinase 3 ⁇ (GSK3 ⁇ ) (Martinez et al. (2002) Med Res Rev.22(4): 373-384; Martinez et al. (2002) J Med Chem.45(6): 1292-1299; Martinez et al. (2005) J Med Chem.48(23): 7103-7112), opening of potassium channels (Mart ⁇ nez et al.
- Celecoxib another anti-inflammatory drug designed as a selective COX-2 inhibitor, also moderately extends C. elegans life span while reducing protein aggregation (Ching et al. (2011) Aging Cell.10(3): 506-519).
- anti-inflammatory, nonselective cyclo-oxygenase inhibitors such as aspirin, parthenolides, TDZD analogs, and the selective COX-2 inhibitor ibuprofen, may all share the ability to relieve diverse age-associated conditions by reducing protein aggregation.
- the TDZD ring system was also modified by introducing diverse alkyl and heterocyclic amine groups of varying chain length. More importantly from a drug-design perspective, ⁇ NH 2 and/or ⁇ OH groups were introduced to the thiadiazolidinone (TDZD) moiety in order to create drugs with improved water solubility, bioavailability, and tissue targeting.
- TDZD analogs produce rapid cell-death kinetics in leukemia cells but not in normal bone marrow cells
- several TDZD-8 analogs are reported as potent anti-leukemic agents (Guzman et al. (2007) Blood.110(13): 4436-4444; Nasim et al. (2011) Bioorg Med Chem Lett.21(16): 4879-4883).
- Sesquiterpene lactones have been isolated from many species of medicinal plants (Chaturvedi D. Sesquiterpene lactones: structural diversity and their biological activities, In- Opportunity, Challanges and Scope of Natural Products in Medicinal Chemistry.
- PTL and its derivatives promote apoptosis by inhibiting the activity of the NF- ⁇ B transcription factor complex, thereby downregulating anti-apoptotic genes under NF- ⁇ B control and also increasing reactive oxygen species (ROS) through inhibition of the glutathione pathway (Bork et al. (1997) FEBS Lett.402(1): 85-90; Wen et al. (2002) J Biol Chem.277(41): 38954-38964; Hehner et al. (1998) J Biol Chem.273(3): 1288-1297; Sweeney et al.
- ROS reactive oxygen species
- AML is a clonal malignancy of the hematopoietic system characterized by accumulation of immature cell populations in the bone marrow or peripheral blood (Deschler and Lubbert (2006) Cancer.107(9): 2099-2107).
- AML is the most common leukemia in adults and has the lowest survival rate of all leukemias (Estey and Döhner (2006) The Lancet.368(9550): 1894-1907; Löwenberg et al. (1998) Journal of Clinical Oncology. 16(3): 872-881; Tazzari et al. (2007) Leukemia.21(3): 427-438).
- MMB melampomagnolide B
- MMB has been identified as a new antileukemic sesquiterpene with properties similar to PTL.
- MMB was synthesized utilizing a modification of the method of Macias et al. via selenium oxide oxidation of the C10 methyl group of PTL, which also results in concomitant conversion of the geometry of the C9–C10 double bond from trans to cis orientation (Mac ⁇ as et al. (1992) Phytochemistry. 31(6): 1969-1977).
- a biotin-conjugated derivative of MMB was designed and synthesized in order to elucidate its mechanism of action (Nasim et al.
- MMB is a more interesting molecule because it contains a primary ⁇ OH group, which provides the means to design prodrugs with improved water solubility, bioavailability, and tissue targeting.
- MMB itself is less potent against leukemia cell lines than its parent molecule PTL and also against solid tumor cell lines. More recently the anti-cancer activity of MMB was enhanced by synthesizing a variety of carbamate (Janganati et al. (2014) Bioorg Med Chem Lett.24(15): 3499-3502; Janganati et al.
- MMB- TDZD conjugated analogs have also been designed and synthesized as potent anti-cancer and anti-aging compounds. [0009]
- the design and synthesis of novel conjugated analogs having improved potency and selectivity continues to remain elusive.
- the invention in one aspect, relates to compounds and compositions for use in the prevention and treatment of neurodegenerative diseases (e.g., sarcopenia, supranuclear palsy, Alzheimer’s disease, dementia) and disorders of uncontrolled cellular proliferation such as, for example, cancer (e.g., sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas)).
- cancer e.g., sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer,
- R 1 is selected from C1 -C10 alkyl, C2-C10 alkenyl, C1 -C10 haloalkyl, C1 -C10 cyanoalkyl, C1 -C10 nitroalkyl, C1 -C10 hydroxyalkyl, C1 -C10 alkoxy, C1- C10 alkenoxy, C1 -C10 thioalkyl, C1 -C10 alkylthiol, C1 -C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1 -C10 aminoalkyl, -(C1 -C10 alkyl)-O-(C 1 -C 10 alkyl), -(C1 -C10 alkyl)C(O)R 10 , -(C1 -C10 alkyl)OC(
- R 1 is C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 haloalkyl, and one of R 2a , R 2b , R 2c , R 2d , and R 2e is , then R 11 is not -OC(O) 2 (C1-C8 alkyl), ⁇ NHC(O) 2 (C1-C8 alkyl), or ⁇ N(C1-C4 alkyl)C(O) 2 (C1-C8 alkyl), or a pharmaceutically acceptable salt thereof.
- R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)OC(O)(C1-C10 alkyl), ⁇ (
- a compound having a structure or a pharmaceutically acceptable salt thereof.
- a compound having a structure or a pharmaceutically acceptable salt thereof.
- R1 refers to H or different straight or branched chain hydrocarbyl groups or substituted hydrocarbyl with carbon numbers ranging from 0 to 10; or alkyl halides; or alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thiol or diverse hetero-aromatic or other aromatic ring, where halogen refers to F, Cl, Br
- Y refers to only H or Cl or Br, or I, or R2 also refers to different aromatic or hetero- aromatic ring systems like 1-naphthyl or 2-naphthyl group; different simple and substituted 2/3- furyl; 2 or 3 or 4 or 5 or 6 or 7-benzofuryl; 2 or 4 or 5-oxazolyl; 3 or 4 or 5-isoxazolyl; 4 or 5- oxadiazolyl, 2 or 4 or 5 or 6 or 7-benzoxazolyl; 4 or 5 or 6 or 7-benzoxadiazolyl; 2 or 3-pyrrolyl; 3 or 4 or 5-pyrazolyl; 2 or 4 or 5-imidazolyl; 2 or 3 or 4 or 5 or 6 or 7-quinolyl; 2 or 4 or 5 or 6 or 7-quinazolyl; 3 or 4 or 5 or 6 or 7-indazolyl; 4 or 5-triazolyl; 5-tetrazolyl; 2 or 3 or 4 pyridyl; 2 or 4
- compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
- methods for treating a disorder of uncontrolled cellular proliferation in a subject comprising administering to the subject an effective amount of a disclosed compound.
- methods for treating a neurological disorder in a subject comprising administering to the subject an effective amount of a disclosed compound.
- methods for treating a neurological disorder in a subject comprising administering to the subject an effective amount of a compound selected from:
- kits comprising a disclosed compound, and one or more of: (a) at least one agent associated with the treatment of a disorder of uncontrolled cellular proliferation; (b) at least one agent associated with the treatment of a neurological disorder; (c) instructions for administering the compound in connection with treating a disorder of uncontrolled cellular proliferation; (d) instructions for administering the compound in connection with treating a neurological disorder; (e) instructions for treating a disorder of uncontrolled cellular proliferation; and (f) instructions for treating a neurological disorder.
- FIG.1 shows a generic chemical structure of 2,4-substituted thiadiazolidinones (TDSDs).
- FIG.2 shows the chemical structure of parthenolide (PTL).
- FIG.3 shows the chemical structure of melampomagnolide B (MMB).
- FIG.4 shows representative data illustrating that PNR-962 (5 ⁇ M) reduces protein aggregation in human neuroblastoma cells (SH-SY5Y-APP Sw ) that express APP Sw , an aggregation-prone mutant form of amyloid precursor protein.
- FIG.5 shows representative data illustrating that a GSK-3 inhibitor reduces paralysis >75% in C. elegans adults with muscle expression of A ⁇ 1–42 . Specifically, the percent of worms paralyzed 48 hr after induction of A ⁇ 1–42 synthesis, by upshift to 25 °C at the L3/L4 transition, is shown. Significance, as shown, was assessed by a 2-tailed heteroscedastic t test.
- FIG.6 shows representative data demonstrating that PNR-962, a TDZD analogue, reduces huntingtin-like aggregates in a C. elegans Huntington’s disease-model strain Specifically, adult worms expressing Q40::YFP were imaged and YFP + muscle aggregates were quantified after 3 days of exposure to 5- ⁇ M PNR-962. Treated worms differ from controls by 2- tailed t test (P ⁇ 0.0001).
- FIG.7 shows representative data demonstrating that the number of aggregation foci decreases with exposure to PNR-962 (a GSK-3 ⁇ inhibitor), or to an (aspirin + GSK-3 ⁇ inhibitor) combo drug (BSK-179) in a C.
- FIG.8 shows representative data demonstrating that the lifespan of C. elegans is increased by aspirin, PNR-962, or BSK-179
- FIG.9 shows representative data illustrating that BSK-179 reduces amyloid accumulation in human neuroblastoma cells expressing mutant amyloid precursor protein (APPSw). Amyloid foci were stained with thioflavin T in SH-SY5Y-APPSw cells treated for 2 days.
- FIG.10 shows the chemical structures of aspirin and BSK-179.
- FIG.11 shows a representative image illustrating a proposed binding conformation of TDZD analogues to GSK3 ⁇ .
- FIG.12 shows representative data generated from a virtual screen against GSK3 ⁇ .
- FIG.13 shows representative data pertaining to a SeeSAR structure-activity analysis of TDZD-GSK3 ⁇ .
- FIG.14 shows representative data pertaining to the in vitro screening of TDZD analogues in HEK-TAU cells (by thioflavin-T staining).
- FIG.15 shows representative data demonstrating the potency of TDZD analogues.
- FIG.16 shows a representative image generated via computational modeling of TDZD analogues.
- FIG.17 shows further representative data demonstrating the potency of TDZD analogues.
- FIG.18A-G shows representative data illustrating a computer prediction that PNR886 and PNR962 bind stably to the same allosteric hydrophobic pocket in GSK3 ⁇ .
- FIG.19A-I show representative snapshots of full-length GSK3 ⁇ bound to TDZD-8 (FIG.19A-C) and its analogs PNR962 (FIG.19D-F) and PNR886 (FIG.19G-I).
- FIG.19J-L show representative data illustrating the root mean square deviation (RMSD) of protein-ligand complexes during 200-ns simulations of GSK3 ⁇ binding to TDZD-8 (FIG.
- RMSD root mean square deviation
- FIG.20 shows representative data illustrating that TDZD analogs bind to GSK3 ⁇ in MM/GBSA assay.
- FIG.21A-C show representative dose-response curves for in vitro inhibition of GSK3 ⁇ activity by TDZ-8 (FIG.21A), PNR962 (FIG.21B), and PNR886 (FIG.21C).
- FIG.22 shows representative data illustrating the superimposition of drugs for QSAR modeling and prediction.
- FIG.23 shows representative data illustrating the suppression of tau hyperphosphorylation by PNR962, a TDZD analogue.
- the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ⁇ 10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
- an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
- References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
- X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
- a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
- IC50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
- an IC 50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein.
- IC50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.
- EC50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
- a substance e.g., a compound or a drug
- an EC 50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein.
- EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.
- the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
- the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
- the subject of the herein disclosed methods can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex.
- the subject is a mammal.
- a patient refers to a subject afflicted with a disease or disorder.
- the term “patient” includes human and veterinary subjects.
- treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
- This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
- this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
- the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
- the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
- subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
- livestock e.g., cattle, horses, pigs, sheep, goats, etc.
- laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
- the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
- the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject.
- Such methods include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
- a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
- a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
- the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
- a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
- the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
- compositions can contain such amounts or submultiples thereof to make up the daily dose.
- the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition. [0067]
- “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject.
- a dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques.
- Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-phen
- a dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.
- kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.
- instruction(s) means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.
- therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
- the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
- therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
- the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-cancer and anti-neoplastic agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra- terminal (BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programme
- the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
- therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
- pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
- the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
- exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
- the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
- suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
- These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
- Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
- Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
- Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
- biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which
- Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
- the term “substituted” is contemplated to include all permissible substituents of organic compounds.
- the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
- Illustrative substituents include, for example, those described below.
- the permissible substituents can be one or more and the same or different for appropriate organic compounds.
- the heteroatoms such as nitrogen
- the heteroatoms can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
- This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds.
- substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
- substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
- a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
- aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1- 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
- alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
- the alkyl group can be cyclic or acyclic.
- the alkyl group can be branched or unbranched.
- the alkyl group can also be substituted or unsubstituted.
- the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
- a “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
- alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
- alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
- halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
- halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
- monohaloalkyl specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
- polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e.
- alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
- aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
- hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
- alkyl is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0079] This practice is also used for other groups described herein.
- cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
- the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
- a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
- a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
- cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms.
- examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
- heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
- the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
- the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
- the term “polyalkylene group” as used herein is a group having two or more CH 2 groups linked to one another.
- the polyalkylene group can be represented by the formula —(CH 2 ) a —, where “a” is an integer of from 2 to 500.
- Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA 1 —OA 2 or —OA 1 —(OA 2 )a—OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
- alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
- the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
- groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described here
- Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
- heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
- the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
- the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
- alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
- the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
- groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or
- cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
- cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
- heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
- the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
- the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
- aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
- aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference.
- aromatic group is inclusive of both aryl and heteroaryl groups.
- aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
- the aryl group can be substituted or unsubstituted.
- the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ⁇ NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
- biasryl is a specific type of aryl group and is included in the definition of “aryl.”
- the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond.
- biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
- aldehyde as used herein is represented by the formula —C(O)H.
- amine or “amino” as used herein are represented by the formula —NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ⁇ NH 2 .
- alkylamino as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein.
- dialkylamino as used herein is represented by the formula —N(-alkyl) 2 where alkyl is a described herein.
- Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.
- carboxylic acid as used herein is represented by the formula —C(O)OH.
- esteer as used herein is represented by the formula —OC(O)A 1 or —C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
- polyester as used herein is represented by the formula —(A 1 O(O)C-A 2 -C(O)O)a— or —(A 1 O(O)C-A 2 -OC(O))a—, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
- ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
- polyether as used herein is represented by the formula —(A 1 O-A 2 O) a —, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500.
- Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
- halo halogen
- halide as used herein can be used interchangeably and refer to F, Cl, Br, or I.
- pseudohalide pseudohalogen
- pseudohalo pseudohalogen
- pseudohalo can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
- heteroalkyl refers to an alkyl group containing at least one heteroatom.
- heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
- Heteroalkyls can be substituted as defined above for alkyl groups.
- heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
- the heteroaryl group can be substituted or unsubstituted.
- heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
- Heteroaryl groups can be monocyclic, or alternatively fused ring systems.
- Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
- heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
- heterocycle or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
- Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5- oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4- tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including
- heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2- C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
- a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
- a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.
- bicyclic heterocycle or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
- Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
- Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
- Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3- c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.
- heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
- the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
- heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
- hydroxyl or “hydroxyl” as used herein is represented by the formula —OH.
- ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
- Azide or “azido” as used herein is represented by the formula —N3.
- nitro as used herein is represented by the formula —NO 2 .
- nitrile or “cyano” as used herein is represented by the formula —CN.
- sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
- sulfo-oxo is represented by the formulas —S(O)A 1 , — S(O) 2 A 1 , —OS(O) 2 A 1 , or —OS(O) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
- sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula —S(O) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
- a 1 S(O) 2 A 2 is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
- sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
- thiol as used herein is represented by the formula —SH.
- R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
- R 1 is a straight chain alkyl group
- one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
- a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
- an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
- the amino group can be attached to the backbone of the alkyl group.
- the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
- compounds of the invention may contain “optionally substituted” moieties.
- substituted whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent.
- an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
- Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
- individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
- Suitable monovalent substituents on R ⁇ are independently halogen, —(CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0– 2CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), –CN, –N3, –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , – (CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , –(CH 2 ) 0
- Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2) 2 –3O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on the aliphatic group of R * include halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , – S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2, –C(S)NR ⁇ 2, –C(NH)NR ⁇ 2, or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of
- Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- the term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
- suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
- the terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
- hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).
- organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
- Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like.
- organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
- Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
- an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.
- a very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
- a 2,4- thiazolidinedione radical in a particular compound has the structure: , regardless of whether thiazolidinedione is used to prepare the compound.
- the radical for example an alkyl
- the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
- Organic radicals contain one or more carbon atoms.
- An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
- an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2- 8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
- Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
- an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
- an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
- organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
- organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
- Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.
- a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
- Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
- the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included.
- stereoisomers For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non- superimposable mirror images of one another.
- a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
- a 50:50 mixture of enantiomers is referred to as a racemic mixture.
- Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*).
- bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
- bonds to the chiral carbon when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
- the Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
- the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
- a further step can liberate the desired enantiomeric form.
- specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
- Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.).
- Enantiomeric excess is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%.
- the designated enantiomer is substantially free from the other enantiomer.
- the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms.
- “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.
- a disclosed compound When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
- the pairs of enantiomers e.g., (S,S)/(R,R)
- the stereoisomers that are not mirror-images e.g., (S,S) and (R,S) are diastereomers.
- the diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.
- the compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med.
- “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof.
- the “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates.
- radio-actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine- 18, and the like.
- Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
- the disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
- isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, respectively.
- Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
- Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
- Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
- Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. [00134]
- the compounds described in the invention can be present as a solvate.
- the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
- the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
- one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
- the invention includes all such possible solvates.
- co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
- One or more components of this molecular complex provide a stable framework in the crystalline lattice.
- the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co- crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid. [00136] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an ⁇ -hydrogen can exist in an equilibrium of the keto form and the enol form.
- amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form.
- pyrazoles can exist in two tautomeric forms, N 1 -unsubstituted, 3-A 3 and N 1 -unsubstituted, 5-A 3 as shown below. Unless stated to the contrary, the invention includes all such possible tautomers.
- chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties.
- the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable.
- a structure of a compound can be represented by a formula: which is understood to be equivalent to a formula: wherein n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) .
- independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(b) is not necessarily halogen in that instance.
- Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
- the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
- A-D a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention.
- the invention relates to TDZD analogs useful in treating neurodegenerative diseases (e.g., sarcopenia, supranuclear palsy, Alzheimer’s disease, dementia) and disorders of uncontrolled cellular proliferation such as, for example, cancer (e.g., sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas)).
- cancer e.g., sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal
- the compounds are useful in the treatment of neurodegenerative diseases, as further described below. [00146] In one aspect, the compounds are useful in the treatment of disorders of uncontrolled cellular proliferation, as further described herein. [00147]
- the compound may be a free form or a salt form. When the compound is in a salt form, the salt is preferably a pharmaceutically acceptable salt.
- Pharmaceutically acceptable salts may include, without limitation, hydrochloride, hydrobromide, phosphate, sulfate, methane- sulfonate, acetate, formate, tartrate, bitartrate, stearate, phthalate, hydroiodide, lactate, monohydrate, mucate, nitrate, phosphate, salicylate, phenylpropionate, isobutyrate, hypophosphite, maleic acid, malic acid, citrate, isocitrate, succinate, lactate, gluconate, glucuronate, pyruvate, oxalate, fumarate, propionate, aspartate, glutamate, benzoate, terephthalate, and the like.
- the pharmaceutical acceptable salt includes an alkaline or alkaline earth metal ion salt.
- sodium, potassium or other pharmaceutically acceptable inorganic salts are used.
- each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1.
- STRUCTURE [00149] In one aspect, disclosed are compounds having a structure represented by a formula: wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)OC(O)(C1-C
- m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)OC(O)(C1-C10 alkyl),
- a compound having a structure: or a pharmaceutically acceptable salt thereof in one aspect, disclosed is a compound having a structure: or a pharmaceutically acceptable salt thereof.
- the compound has a structure represented by a formula: In a further aspect, m is 1 and R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 .
- the compound has a structure represented by a formula:
- the compound has a structure represented by a formula: In a further aspect, m is 1, X is NH, and R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 . [00156] In various aspects, the compound has a structure represented by a formula: In a further aspect, m is 1, X is NH, and R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 . [00157] In various aspects, the compound has a structure represented by a formula:
- m is 1, X is NH, and R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 .
- the compound has a structure represented by a formula: wherein each of R 30a and R 30b is independently selected from hydrogen and halogen.
- m is 1, X is NH, and R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 .
- the compound has a structure represented by a formula:
- R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 .
- R 2c is .
- R 11 is selected from:
- R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 , R 2c is , and R 11 is selected from:
- X is selected from NH and O; wherein each of R 30a and R 30b is independently selected from hydrogen and halogen.
- the compound is selected from:
- the compound is selected from: [00162] In one aspect, m is 0, 1, 2, or 3. In a further aspect, m is 0, 1, or 2. In a still further aspect, m is 0 or 1. In yet a further aspect, m is 1 or 2. In an even further aspect, m is 2 or 3. In a still further aspect, m is 1, 2, or 3. In yet a further aspect, m is 3. In an even further aspect, m is 2. In a still further aspect, m is 1. In yet a further aspect, m is 0. a. X GROUPS [00163] In one aspect, X is selected from NH and O. In a further aspect, X is NH. In a still further aspect, X is O.
- R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)OC(O)(C1-C10 alkyl), ⁇ (C1-C10 alkyl)NHC(O)
- R 1 is selected from C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl, C1-C8 cyanoalkyl, C1-C8 nitroalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkenoxy, C1-C8 thioalkyl, C1-C8 alkylthiol, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8 aminoalkyl, ⁇ (C1-C8 alkyl) ⁇ O ⁇ (C1-C8 alkyl), ⁇ (C1-C8 alkyl)C(O)R 10 , ⁇ (C1-C8 alkyl)OC(O)(C1-C8 alkyl), ⁇ (C1-C8 alkyl)NHC(O)(C1-C8 alkyl),
- R 1 is selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 nitroalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkenoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl), ⁇ (C1-C4 alkyl)C(O)R 10 , ⁇ (C1-C4 alkyl)OC(O)(C1-C4 alkyl), ⁇ (C1-C4 alkyl)NHC(O)(C1-C4 alkyl),
- R 1 is selected from C1-C8 alkyl, C2-C8 alkenyl, C1-C8 haloalkyl, ⁇ (C1-C8 alkyl) ⁇ O ⁇ (C1-C8 alkyl), ⁇ (C1-C8 alkyl)C(O)R 10 , ⁇ (C1-C8 alkyl)OC(O)(C1-C8 alkyl), ⁇ (C1-C8 alkyl)NHC(O)(C1-C8 alkyl), ⁇ (C1-C8 alkyl)N(C1-C8 alkyl)C(O)(C1-C8 alkyl), ⁇ (C1-C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl), ⁇ (C1-C4 alkyl)C(O)R 10 , ⁇ (C1-C4 alkyl)OC(O)(C1-C4 alkyl), ⁇ (C1-C4 alkyl)NHC(O)(C1-C4 alkyl), ⁇ (C1-C4 alkyl)N(C1-C4 alkyl)C(O)(C1-C4 alkyl), ⁇ (C1-C4)Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, —CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, – CH 2 CH 2 CH 2 F, –CH(CH 3 ) 2 Cl, –CH(CH 3 ) 2 F, ⁇ CH 2 OCH 3 , ⁇ CH 2 CH 2 OCH 3 , ⁇ CH 2 OCH 2 CH 3 , ⁇ CH 2 CH 2 CH 2 OCH 2 CH 3 , ⁇ CH 2 CH 2 OCH(CH 3 ) 2 , ⁇ CH 2 C(O)R 10 , ⁇ CH 2 CH 2 C(O)R 10 , ⁇ CH 2 CH 2 C(O)R 10 , ⁇ CH(CH 3 )CH 2 C(O)R 10 , ⁇ CH 2 OC(O)
- R 1 is selected from methyl, ethyl, ethenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, ⁇ CH 2 OCH 3 , ⁇ CH 2 CH 2 OCH 3 , ⁇ CH 2 OCH 2 CH 3 , ⁇ CH 2 C(O)R 10 , ⁇ CH 2 CH 2 C(O)R 10 , ⁇ CH 2 OC(O)CH 3 , ⁇ CH 2 CH 2 O(CO)CH 3 , ⁇ CH 2 OC(O)CH 2 CH 3 , ⁇ CH 2 NHC(O)CH 3 , ⁇ CH 2 CH 2 NHC(O)CH 3 , ⁇ CH 2 NHC(O)CH 2 CH 3 , ⁇ CH 2 N(CH 3 )C(O)CH 3 , ⁇ CH 2 CH 2 N(CH 2 CH 3 )C(O)CH 3 , ⁇ CH 2 CH 2 N(CH 2 CH 3 )C(O)CH 3 , —
- R 1 is selected from methyl, –CH 2 Cl, –CH 2 F, ⁇ CH 2 OCH 3 , ⁇ CH 2 C(O)R 10 , ⁇ CH 2 OC(O)CH 3 , ⁇ CH 2 NHC(O)CH 3 , ⁇ CH 2 N(CH 3 )C(O)CH 3 , – CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from C1-C10 alkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, ⁇ (C1-C10)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C8 alkyl, C1-C8 cyanoalkyl, C1-C8 nitroalkyl, ⁇ (C1-C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 nitroalkyl, ⁇ (C1-C4)Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, n-propyl, isopropyl, –CH 2 CN, –CH 2 CH 2 CN, – CH 2 CH 2 CH 2 CN, –CH(CH 3 ) 2 CN, –CH 2 NO 2 , –CH 2 CH 2 NO 2 , –CH 2 CH 2 CH 2 NO 2 , –CH(CH 3 ) 2 NO 2 , –CH 2 Cy 1 , –CH 2 CH 2 Cy 1 , –CH 2 CH 2 CH 2 Cy 1 , –CH(CH 3 ) 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 NO 2 , –CH 2 CH 2 NO 2 , –CH 2 Cy 1 , – CH 2 CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, –CH 2 CN, –CH 2 NO 2 , –CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from C1-C10 alkyl, C1-C10 hydroxyalkyl, C1- C10 alkoxy, C1-C10 alkenoxy, ⁇ (C1-C10)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkenoxy, ⁇ (C1-C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkenoxy, ⁇ (C1-C4)Cy 1 , and Cy 1 .
- R 1 is selected from methyl, –CH 2 OH, – OCH 3 , –CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from C1-C10 alkyl, C1-C10 thioalkyl, C1-C10 alkylthiol, ⁇ (C1-C10)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 alkylthiol, ⁇ (C1-C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, C1-C4 thioalkyl, C1-C4 alkylthiol, ⁇ (C1-C4)Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, n-propyl, isopropyl, –CH 2 SH, –CH 2 CH 2 SH, –CH 2 CH 2 CH 2 SH, —CH(CH 3 ) 2 SH, –SCH 3 , –SCH 2 CH 3 , –SCH 2 CH 2 CH 3 , –SCH 2 (CH 3 ) 2 , –CH 2 Cy 1 , –CH 2 CH 2 Cy 1 , – CH 2 CH 2 CH 2 Cy 1 , –CH(CH 3 ) 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, –CH 2 SH, –CH 2 CH 2 SH, –SCH 3 , –SCH 2 CH 3 , –CH 2 Cy 1 , –CH 2 CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, –CH 2 SH, –SCH 3 , –CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from C1-C10 alkyl, C1-C10 alkylamino, (C1- C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C8 alkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8 aminoalkyl, ⁇ (C1-C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ (C1-C4)Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, n-propyl, isopropyl, –CH 2 NH 2 , – CH 2 CH 2 NH 2 , –CH 2 CH 2 CH 2 NH 2 , –CH(CH 3 ) 2 NH 2 , –NHCH 3 , –NHCH 2 CH 3 , –NHCH 2 CH 2 CH 3 , – NHCH 2 (CH 3 ) 2 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , –N(CH 3 )CH 2 CH 2 CH 3 , –N(CH 3 )CH 2 (CH 3 ) 2 , – CH 2 Cy 1 , –CH 2 CH 2 Cy 1 , –CH 2 CH 2 CH 2 Cy 1 , –CH(CH 3 ) 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , –NHCH 3 , –NHCH 2 CH 3 , – NHCH 2 (CH 3 ) 2 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , –CH 2 Cy 1 , –CH 2 CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, –CH 2 NH 2 , –NHCH 3 , –NHCH 2 (CH 3 ) 2 , –N(CH 3 ) 2 , –CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from C1-C10 alkyl, ⁇ (C1-C10)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C8 alkyl, ⁇ (C1-C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, ⁇ (C1-C4)Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, n-propyl, isopropyl, –CH 2 Cy 1 , –CH 2 CH 2 Cy 1 , –CH 2 CH 2 CH 2 Cy 1 , – CH(CH 3 ) 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, –CH 2 Cy 1 , – CH 2 CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl,–CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, ⁇ (C1- C10)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C8 alkyl, C1-C8 haloalkyl, ⁇ (C1- C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, C1-C4 haloalkyl, ⁇ (C1- C8)Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, n-propyl, isopropyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 ) 2 Cl,– CH(CH 3 ) 2 F, ⁇ CH 2 Cy 1 , ⁇ CH 2 CH 2 Cy 1 , ⁇ CH 2 CH 2 CH 2 Cy 1 , ⁇ CH(CH 3 ) 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, ethyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, ⁇ CH 2 Cy 1 , ⁇ CH 2 CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from methyl, –CH 2 Cl, –CH 2 F, ⁇ CH 2 Cy 1 , and Cy 1 .
- R 1 is selected from C1-C10 alkyl, C1-C10 haloalkyl, and Cy 1 .
- R 1 is selected from C1-C8 alkyl, C1-C8 haloalkyl, ⁇ (C1-C8)Cy 1 , and Cy 1 .
- R 1 is selected from C1-C4 alkyl, C1-C4 haloalkyl, and Cy 1 .
- R 1 is selected from methyl, ethyl, n-propyl, isopropyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,– CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 ) 2 Cl, –CH(CH 3 ) 2 I, –CH(CH 3 ) 2 F, and Cy 1 .
- R 1 is selected from methyl, ethyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,– CH 2 CH 2 F, and Cy 1 .
- R 1 is selected from methyl, –CH 2 Cl, –CH 2 F, and Cy 1 .
- R 1 is Cy 1 . c. R 2A , R 2B , R 2C , R 2D , AND R 2E GROUPS
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dial
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, ethyl, n-propyl, isopropyl, Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, ethyl, Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected m hydrogen, halogen, Ar , and a structure R 11 fro 1 having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, ⁇ Br, ⁇ Cl, ⁇ F, Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, ⁇ Cl, ⁇ F, Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, ⁇ F, Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , Ar 1 , and a structure having a formula: .
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from -F, -Cl, -CN, -NH 2 , -OH, -NO 2 , -OC(O)CH 3 , Ar 1 , and a structure having a formula:
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, halogen, -CN, -NH 2 , -OH, -NO 2 , C1-C4 alkyl, C2-C4 alkenyl, Ar 1 , and a structure having a formula:
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, -F, -Cl, -CN, -NH 2 , -OH, -NO 2 , methyl, ethyl, n- propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, Ar 1 , and a structure having a formula:
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, halogen, -CN, -NH 2
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, halogen, -CN, -NH 2 , -OH, -NO 2 , C1-C4 haloalkyl, C1-C4 cyanoalkyl, Ar 1 , and a structure having a formula:
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, -F, -Cl, -CN, -NH 2 , -OH, -NO 2 , -CH 2 CI, -CH 2 F, - CH 2 CH 2 CI, -CH 2 CH 2 F, -CH 2 CH 2 CH 2 CI, -CH(CH 3 )CH 2 C1, -CH(CH 3 )CH 2 F, - CH 2 CN, -CH 2 CH
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, -F, -Cl, -CN, -NH 2 ,
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, halogen, -CN, -NH 2 , -OH, -NO 2 , C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl-
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, -F, -Cl, -CN, -NH 2 , -OH, -NO 2 , - CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -OCH 2 CI, -OCH 2 F, - OCH 2 CH 2 CI, -OCH 2 CH 2 F, -OCH 2 CH 2 CH 2 CI, -OCH 2 CH 2 CH 2 F, 0CH(CH 3 )CH 2 C1, - OCH(CH 3 )CH 2 F, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , Ar 1 , and a structure
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, -F, -Cl, -CN, -NFh, -OH, -NO 2 , -CH 2 OH, -OCH 2 CI,
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, halogen, -CN, -NH 2 , -OH, -NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Cl -C4 aminoalkyl, Ar 1 , and a structure having a formula 2 b ,: .
- each of R 2a , R , R 2c , R > 2 2 d d , and R 2e is independently selected from hydrogen, -F, -Cl, -
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, -
- each of R 2a , R 2b , R 2c , R 2d , and R 2e is independently selected from hydrogen, -F, -Cl, -CN, -NH 2 , -
- R 2a , R 2b , R 2c , R 2d , and R 2e is selected from Ar 1 and and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, halogen, -CN, -NH 2 , -OH, -NO2, -OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-
- R 2a , R 2b , R 2c , R 2d , and R 2e is selected from Ar 1 and and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, -F, -Cl, -CN, -NH 2 , -OH, -NO 2 , -OC(O)CH 3 , - OC(O)CH 2 CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, -CH 2 CI, -CH 2 F, -CH 2 CH 2 CI, -CH 2 CH 2 F, -CH 2 CH 2 CH 2 CI, - CH 2 CH 2 CH 2 F, -CH(CH 3 )CH 2 C1, -CH
- one of R 2a , R 2b , R 2c , R 2d , and R 2e is selected from Ar 1 and and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, -
- one of R 2a , R 2b , R 2c , R 2d , and R 2e is selected from Ar 1 and and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, -F, -Cl, -CN, -NH 2 , -OH, -NO 2 , -OC(O)CH 3 , methyl, -CH 2 CI, -CH 2 F, -CH 2 CN, -CH 2 OH, -OCH 2 CI, -OCH 2 F, -OCH 3 , -CH 2 NH 2 , -NHCH 3 , and -
- R 2c is selected from Ar 1 and and R 2a , R 2b , R 2d , and
- R 2e are independently selected from hydrogen, halogen, -CN, -NH?, -OH, -NO 2 , -OC(O)(C1- C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- R 2c is selected from Ar 1 and and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, -F, -Cl, -CN, -NH 2 , -OH, -NO 2 , -OC(O)CH 3 , -OC(O)CH 2 CH 3 , -OC(O)CH(CH 3 ) 2 , -OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n- propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, -CH 2 CI, -CH 2 F, -CH 2 CH 2 CI, -CH 2 CH 2 F, - CH 2 CH 2 CH 2 CI, -CH 2 CH 2 CH 2 F, -CH(CH 3 )CH 2 C1, -CH(CH 3 )CH 2 F, -CH 2 CN, -CH 2 CH 2 CN
- R 2c is selected from Ar 1 and 2a 2b and R , R , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , —CH 2 NH 2 , –CH 2 CH 2 NH 2 , –NHCH 3 , –NHCH 2 CH 3 , —NHCH 2 CH 3
- R 2c is selected from Ar 1 and and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , methyl, –CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 3 , – CH 2 NH 2 , –NHCH 3 , and –N(CH 3 ) 2 .
- one of R 2a , R 2b , R 2c , R 2d , and R 2e is and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- one of R 2a , R 2b , R 2c , R 2d , and R 2e is and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, – CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 )CH 2 Cl, – CH(CH 2 F, –CH(CH 3 )CH 2 Cl, – CH(CH
- one of R 2a , R 2b , R 2c , R 2d , and R 2e is and four of R 2a , R 2b , R 2c , R 2d , 2 e and R are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , –CH 2 NH 2 , –
- one of R 2a , R 2b , R 2c , R 2d , and R 2e is and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , methyl, –CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 3 , –CH 2 NH 2 , –NHCH 3 , and –N(CH 3 ) 2 .
- R 2c is and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- R 2c is and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, – CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 )CH 2 Cl, – CH(CH 3 )CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 CH 2 CH 2 CH 2 CH 2 CH
- R 2c is and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, – CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , —CH 2 NH 2 , –CH 2 CH 2 NH 2 , –NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 ,
- R 2c is and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , methyl, –CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 3 , –CH 2 NH 2 , –NHCH 3 , and –N(CH 3 ) 2 .
- R 2a , R 2b , R 2c , R 2d , and R 2e is Ar 1 and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- R 2a , R 2b , R 2c , R 2d , and R 2e is Ar 1 and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, –CH 2 Cl, –CH 2 F, – CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 )CH 2 Cl, –
- R 2a , R 2b , R 2c , R 2d , and R 2e is Ar 1 and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, – CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , —CH 2 NH 2 , –
- one of R 2a , R 2b , R 2c , R 2d , and R 2e is Ar 1 and four of R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , methyl, –CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 3 , –CH 2 NH 2 , –NHCH 3 , and – N(CH 3 ) 2 .
- R 2c is Ar 1 and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- R 2c is Ar 1 and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, – CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 )CH 2 Cl, – CH(CH 3 )CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 CH 2 CN, –CHCH 2 CH 2 CN, —CHCH 2 CH 2
- R 2c is Ar 1 and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, – CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , —CH 2 NH 2 , –CH 2 CH 2 NH 2 , –NHCH 3 , –NHCH 2 CH 3 , –N(CH
- R 2c is Ar 1 and R 2a , R 2b , R 2d , and R 2e are independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)CH 3 , methyl, –CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCH 3 , –CH 2 NH 2 , –NHCH 3 , and –N(CH 3 ) 2 .
- R 2c is selected from Ar 1 and .
- R 2a is selected from Ar 1 and .
- R 2b is selected from Ar 1 and
- R 2d is selected from Ar 1 and .
- R 2e is selected from Ar 1 and [00189]
- at least one of R 2a , R 2b , R 2c , R 2d , and R 2e is hydrogen.
- at least two of R 2a , R 2b , R 2c , R 2d , and R 2e is hydrogen.
- at least three of R 2a , R 2b , R 2c , R 2d , and R 2e is hydrogen.
- R 2a , R 2b , R 2c , R 2d , and R 2e are hydrogen.
- three of R 2a , R 2b , R 2c , R 2d , and R 2e are hydrogen and one of R 2a , R 2b , R 2c , R 2d , and R 2e is selected from Ar 1 and [00191]
- R 2c is selected from Ar 1 and and each of R 2a , R 2b , R 2d , and R 2e is hydrogen.
- R 2a , R 2b , R 2c , R 2d , and R 2e is [00193] In various aspects, R 2c is . In a further aspect, R 2a is In a still further aspect, R 2b is . In yet a further aspect, R 2d is . In an even further aspect, R 2e is [00194] In various aspects, one of R 2a , R 2b , R 2c , R 2d , and R 2e is Ar 1 . [00195] In various aspects, R 2c is Ar 1 . In a further aspect, R 2a is Ar 1 . In a still further aspect, R 2b is Ar 1 .
- R 2d is Ar 1 .
- R 2e is Ar 1 . d.
- R 3A , R 3B , R 3C , R 3D , AND R 3E G ROUPS [00196]
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 amino
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 )CH 2 Cl, – CH(CH 3 )CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 CH 2 CN, —CH 2 CH 2 CN, —CH 2 CN, —
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, – CH 2 CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl2, ⁇ OCHF2, ⁇ OCCl3, ⁇ OCF3, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , —CH 2 NH 2 , –CH 2 CH 2 NH 2 ,
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl2, ⁇ OCHF2, ⁇ OCCl3, ⁇ OCF3, ⁇ OCH 3 , –CH 2 NH 2 , –NHCH 3 , –N(CH 3 ) 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, C1-C4 hydroxyalkyl, C1-C4 alkylamino, and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Br, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 OH, – CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , – CH 2 CH 2 CH 2 NH 2 , –CH(CH 3 )CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 OH, –CH 2 CH 2 OH, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 OH, –CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)(C1-C4 alkyl), C1-C4 hydroxyalkyl, C1-C4 alkylamino, and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Br, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , –CH 2 CH 2 CH 2 NH 2 , – CH(CH 3 )CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , –CH 2 OH, –CH 2 CH 2 OH, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , –CH 2 OH, –CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 alkylamino, and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, –CH 2 OH, –CH 2 CH 2 OH, – CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , –CH 2 CH 2 CH 2 NH 2 , – CH(CH 3 )CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, methyl, ethyl, ethenyl, –CH 2 OH, –CH 2 CH 2 OH, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, methyl, –CH 2 OH, –CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkylamino, and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, – CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 )CH 2 Cl, – CH(CH 3 )CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 CH 2 CH 2 CN, –CH(CH 3 )CH 2 CN, –CH 2 OH, – CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, —CH 2 NH 2 , –CH 2 CH 2 NH 2 , – CH 2 CH 2 CH 2 NH 2 , –
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, – CH 2 NH 2 , –CH 2 CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 Cl, – CH 2 F, –CH 2 CN, –CH 2 OH, –CH 2 NH 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 OH, – CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl2, ⁇ OCHF2, ⁇ OCCl3, ⁇ OCF3, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 2 CH 2 CH 2 Cl, ⁇ OCH 2 CH 2 CH 2 F, ⁇ OCH(CH 3 )CH 2 Cl, ⁇ OCH(CH 3 )CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , ⁇ OCH 2 CH 2 CH 3 , ⁇ OCH(CH 3 ) 2 , and
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 OH, –CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl 2 , ⁇ OCHF 2 , ⁇ OCCl 3 , ⁇ OCF 3 , ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl2, ⁇ OCHF2, ⁇ OCCl3, ⁇ OCF3, ⁇ OCH 3 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 NH 2 , –CH 2 CH 2 NH 2 , –CH 2 CH 2 CH 2 NH 2 , –CH(CH 3 )CH 2 NH 2 , –NHCH 3 , –NHCH 2 CH 3 , – NHCH 2 CH 2 CH 3 , —NHCH(CH 3 ) 2 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , –N(CH 3 )CH 2 CH 2 CH 3 , – N(CH 3 )CH(CH 3 ) 2 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 NH 2 , – CH 2 CH 2 NH 2 , –NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , and Ar 1 .
- each of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, ⁇ Cl, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, –CH 2 NH 2 , –NHCH 3 , –N(CH 3 ) 2 , and Ar 1 .
- one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and four of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and Ar 1 .
- one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and four of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 CH 2 CH 2
- one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and four of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, CH 2 Cl, –CH 2 F, – CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl 2 , ⁇ OCHF 2 , ⁇ OCCl 3 , ⁇ OC
- one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and four of R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl2, ⁇ OCHF2, ⁇ OCCl3, ⁇ OCF3, ⁇ OCH 3 , –CH 2 NH 2 , –NHCH 3 , – N(CH 3 ) 2 , and Ar 1 .
- R 3c is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and R 3a , R 3b , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and Ar 1 .
- R 3c is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and R 3a , R 3b , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , ⁇ OC(O)CH(CH 3 ) 2 , ⁇ OC(O)CH 2 CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH(CH 3 )CH 2 Cl, – CH(CH 3 )CH 2 F, – CH(CH 3 )CH 2 F, —
- R 3c is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and R 3a , R 3b , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, ethyl, ethenyl, CH 2 Cl, –CH 2 F, – CH 2 CH 2 Cl, –CH 2 CH 2 F, –CH 2 CN, –CH 2 CH 2 CN, –CH 2 OH, –CH 2 CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl2, ⁇ OCHF2, ⁇ OCCl3, ⁇ OCF3, ⁇ OCH 2 CH 2 Cl, ⁇ OCH 2 CH 2 F, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , ⁇ OCH 2 CH
- R 3c is ⁇ CO 2 H, ⁇ CH 2 OH, or ⁇ CH 2 NH 2 and R 3a , R 3b , R 3d , and R 3e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 H, ⁇ OC(O)CH 3 , ⁇ OC(O)CH 2 CH 3 , methyl, CH 2 Cl, –CH 2 F, –CH 2 CN, –CH 2 OH, ⁇ OCH 2 Cl, ⁇ OCH 2 F, ⁇ OCHCl2, ⁇ OCHF 2 , ⁇ OCCl 3 , ⁇ OCF 3 , ⁇ OCH 3 , –CH 2 NH 2 , –NHCH 3 , –N(CH 3 ) 2 , and Ar 1 .
- one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CH 2 OH.
- three of R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen and one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CH 2 OH.
- four of R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen and one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CH 2 OH.
- each of R 3a , R 3b , R 3d , and R 3e are hydrogen, and R 3c is ⁇ CH 2 OH.
- one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CH 2 NH 2 .
- three of R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen and one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CH 2 NH 2 .
- R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen and one of R 3a , R 3b , R 3c , R 3d , and R 3e is ⁇ CH 2 NH 2 .
- each of R 3a , R 3b , R 3d , and R 3e are hydrogen, and R 3c is ⁇ CH 2 NH 2 .
- each of R 3a , R 3b , R 3d , and R 3e are hydrogen.
- R 3c is ⁇ CH 2 OH.
- R 3c is ⁇ CH 2 NH 2 . e.
- R 10 when present, is selected from hydrogen, ⁇ OH, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylamino, and (C1-C10)(C1-C10) dialkylamino.
- R 10 when present, is selected from hydrogen, ⁇ OH, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, and (C1-C8)(C1-C8) dialkylamino.
- R 10 when present, is selected from hydrogen, ⁇ OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino.
- R 10 when present, is selected from hydrogen, ⁇ OH, methyl, ethyl, n-propyl, isopropyl, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , ⁇ OCH 2 CH 2 CH 3 , ⁇ OCH(CH 3 ) 2 , – NHCH 3 , –NHCH 2 CH 3 , –NHCH 2 CH 2 CH 3 , –NHCH(CH 3 ) 2 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , – N(CH 3 )CH 2 CH 2 CH 3 , and –N(CH 2 CH 3 )CH 2 CH 2 CH 3 .
- R 10 when present, is selected from hydrogen, ⁇ OH, methyl, ethyl, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , –NHCH 3 , – NHCH 2 CH 3 , –N(CH 3 ) 2 , and –N(CH 3 )CH 2 CH 3 .
- R 10 when present, is selected from hydrogen, ⁇ OH, methyl, ⁇ OCH 3 , –NHCH 3 , and –N(CH 3 ) 2 .
- R 10 when present, is selected from hydrogen, C1-C10 alkylamino, and (C1-C10)(C1-C10) dialkylamino.
- R 10 when present, is selected from hydrogen, C1-C8 alkylamino, and (C1-C8)(C1-C8) dialkylamino. In a still further aspect, R 10 , when present, is selected from hydrogen, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
- R 10 when present, is selected from hydrogen, –NHCH 3 , –NHCH 2 CH 3 , – NHCH 2 CH 2 CH 3 , —NHCH(CH 3 ) 2 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , –N(CH 3 )CH 2 CH 2 CH 3 , and – N(CH 2 CH 3 )CH 2 CH 2 CH 3 .
- R 10 when present, is selected from hydrogen, –NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 ) 2 , and –N(CH 3 )CH 2 CH 3 .
- R 10 when present, is selected from hydrogen, –NHCH 3 , and –N(CH 3 ) 2 .
- R 10 when present, is selected from hydrogen, ⁇ OH, and C1-C10 alkoxy.
- R 10 when present, is selected from hydrogen, ⁇ OH, and C1-C8 alkoxy.
- R 10 when present, is selected from hydrogen, ⁇ OH, and C1-C4 alkoxy.
- R 10 when present, is selected from hydrogen, ⁇ OH, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , ⁇ OCH 2 CH 2 CH 3 , and ⁇ OCH(CH 3 ) 2 . In an even further aspect, R 10 , when present, is selected from hydrogen, ⁇ OH, ⁇ OCH 3 , and ⁇ OCH 2 CH 3 . In a still further aspect, R 10 , when present, is selected from hydrogen, ⁇ OH, and ⁇ OCH 3 . [00213] In one aspect, R 10 , when present, is selected from hydrogen and C1-C10 alkyl. In a further aspect R 10 , when present, is selected from hydrogen and C1-C8 alkyl.
- R 10 when present, is selected from hydrogen and C1-C4 alkyl. In yet a further aspect, R 10 , when present, is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, R 10 , when present, is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 10 , when present, is selected from hydrogen and methyl. [00214] In various aspects, R 10 , when present, is selected from hydrogen and ⁇ OH. In a further aspect, R 10 , when present, is ⁇ OH. In a still further aspect, R 10 , when present, is hydrogen. f.
- R 11 when present, is a carboxylate residue of a chemotherapeutic agent or a carbamide residue of a chemotherapeutic agent.
- chemotherapeutic agents include, but are not limited to, alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents such as colchicine, vinblastine, paclitaxel (e.g., TAXOL®), and docetaxel; topoisomerase I inhibitors such as camptothecin and topotecan; topoisomerase II inhibitors such as doxorubicin and etoposide; RNA/DNA antimetabolites such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, gemcitabine, capecitabine and thioguanine; antibodies
- the carboxylate or carbamide residue is selected from: wherein X is selected from NH and O; and wherein each of R 30a and R 30b , when present, is independently selected from hydrogen, ⁇ Cl, ⁇ Br, and ⁇ I. [00217] In various aspects, R 11 , when present, is selected from:
- R 20 when present, is selected from hydrogen, ⁇ OH, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylamino, and (C1-C10)(C1-C10) dialkylamino.
- R 10 when present, is selected from hydrogen, ⁇ OH, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, and (C1-C8)(C1-C8) dialkylamino.
- R 20 when present, is selected from hydrogen, ⁇ OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino.
- R 20 when present, is selected from hydrogen, ⁇ OH, methyl, ethyl, n-propyl, isopropyl, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , ⁇ OCH 2 CH 2 CH 3 , ⁇ OCH(CH 3 ) 2 , – NHCH 3 , –NHCH 2 CH 3 , –NHCH 2 CH 2 CH 3 , –NHCH(CH 3 ) 2 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , – N(CH 3 )CH 2 CH 2 CH 3 , and –N(CH 2 CH 3 )CH 2 CH 2 CH 3 .
- R 20 when present, is selected from hydrogen, ⁇ OH, methyl, ethyl, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , –NHCH 3 , – NHCH 2 CH 3 , –N(CH 3 ) 2 , and –N(CH 3 )CH 2 CH 3 .
- R 20 when present, is selected from hydrogen, ⁇ OH, methyl, ⁇ OCH 3 , –NHCH 3 , and –N(CH 3 ) 2 .
- R 20 when present, is selected from hydrogen, C1-C10 alkylamino, and (C1-C10)(C1-C10) dialkylamino. In a further aspect R 20 , when present, is selected from hydrogen, C1-C8 alkylamino, and (C1-C8)(C1-C8) dialkylamino. In a still further aspect, R 20 , when present, is selected from hydrogen, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
- R 20 when present, is selected from hydrogen, –NHCH 3 , –NHCH 2 CH 3 , – NHCH 2 CH 2 CH 3 , —NHCH(CH 3 ) 2 , –N(CH 3 ) 2 , –N(CH 3 )CH 2 CH 3 , –N(CH 3 )CH 2 CH 2 CH 3 , and – N(CH 2 CH 3 )CH 2 CH 2 CH 3 .
- R 20 when present, is selected from hydrogen, –NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 ) 2 , and –N(CH 3 )CH 2 CH 3 .
- R 20 when present, is selected from hydrogen, –NHCH 3 , and –N(CH 3 ) 2 .
- R 20 when present, is selected from hydrogen, ⁇ OH, and C1-C10 alkoxy.
- R 20 when present, is selected from hydrogen, ⁇ OH, and C1-C8 alkoxy.
- R 20 when present, is selected from hydrogen, ⁇ OH, and C1-C4 alkoxy.
- R 20 when present, is selected from hydrogen, ⁇ OH, ⁇ OCH 3 , ⁇ OCH 2 CH 3 , ⁇ OCH 2 CH 2 CH 3 , and ⁇ OCH(CH 3 ) 2 . In an even further aspect, R 20 , when present, is selected from hydrogen, ⁇ OH, ⁇ OCH 3 , and ⁇ OCH 2 CH 3 . In a still further aspect, R 20 , when present, is selected from hydrogen, ⁇ OH, and ⁇ OCH 3 . [00221] In one aspect, R 20 , when present, is selected from hydrogen and C1-C10 alkyl. In a further aspect R 20 , when present, is selected from hydrogen and C1-C8 alkyl.
- R 20 when present, is selected from hydrogen and C1-C4 alkyl. In yet a further aspect, R 20 , when present, is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In an even further aspect, R 20 , when present, is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 20 , when present, is selected from hydrogen and methyl. [00222] In various aspects, R 20 , when present, is selected from hydrogen and ⁇ OH. In a further aspect, R 20 , when present, is ⁇ OH. In a still further aspect, R 20 , when present, is hydrogen. h.
- each of R 30a and R 30b when present, is independently selected from hydrogen, ⁇ Cl, ⁇ Br, and ⁇ I. In a still further aspect, each of R 30a and R 30b , when present, is independently selected from hydrogen, ⁇ Cl, and ⁇ Br. In yet a further aspect, each of R 30a and R 30b , when present, is independently selected from hydrogen and ⁇ Br. In an even further aspect, each of R 30a and R 30b , when present, is independently selected from hydrogen and ⁇ Cl. [00224] In further aspects, each of R 30a and R 30b , when present, is hydrogen.
- each of R 30a and R 30b when present, is ⁇ Cl. In further aspects, each of R 30a and R 30b , when present, is ⁇ Br. In still further aspects, each of R 30a and R 30b , when present, is ⁇ I. i.
- Cy 1 when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is unsubstituted.
- Cy 1 when present, is selected from aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from aryl and heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from aryl and heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from aryl and heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl
- C1-C4 alkyl C2-C4 alkenyl
- Cy 1 when present, is selected from aryl and heteroaryl, and is unsubstituted.
- Cy 1 when present, is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- aryls include, but are not limited to, phenyl, naphthyl, phenanthryl, and anthracenyl.
- Cy 1 when present, is aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl) C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl,
- Cy 1 when present, is unsubstituted aryl.
- Cy 1 when present, is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is C6 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is C6 aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl) C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl,
- Cy 1 when present, is unsubstituted C6 aryl.
- Cy 1 when present, is C6 aryl monosubstituted with a group selected from halogen, ⁇ CN, and C1-C4 alkoxy.
- Cy 1 when present, is C6 aryl monosubstituted with a group selected from ⁇ Cl, ⁇ Br, ⁇ F, ⁇ CN, methoxy, ethoxy, n- propoxy, and isopropoxy.
- Cy 1 when present, is C6 aryl monosubstituted with a group selected from ⁇ Cl, ⁇ F, ⁇ CN, methoxy, and ethoxy. In yet a further aspect, Cy 1 , when present, is C6 aryl monosubstituted with a group selected from ⁇ Cl, ⁇ F, ⁇ CN, and methoxy.
- Cy 1 when present, is selected from: [00231] In various aspects, Cy 1 , when present, is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- heteroaryls include, but are not limited to, pyrrole, furan, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, triazine, purine, oxazole, benzo[d]oxazole, benzo[d]thiazole, indole, and isoxazole.
- Cy 1 when present, is heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is heteroaryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl) C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1
- Cy 1 when present, is unsubstituted heteroaryl.
- Cy 1 when present, is selected from cycloalkyl and heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl and heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl and heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl and heterocycloalkyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is selected from cycloalkyl and heterocycloalkyl, and is unsubstituted.
- Cy 1 when present, is cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is cycloalkyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is cycloalkyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl) C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl
- Cy 1 when present, is unsubstituted cycloalkyl.
- Cy 1 when present, is heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- heterocycloalkyls include, but are not limited to, aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl.
- Cy 1 when present, is heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is heterocycloalkyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Cy 1 when present, is heterocycloalkyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ OC(O)(C1-C4 alkyl) C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl
- Cy 1 when present, is unsubstituted heterocycloalkyl.
- Ar 1 when present, is selected from heteroaryl and aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is selected from heteroaryl and aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is selected from heteroaryl and aryl, and is substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is selected from heteroaryl and aryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-
- Ar 1 when present, is selected from heteroaryl and aryl, and is unsubstituted.
- Ar 1 when present, is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- heteroaryls include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
- heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
- Ar 1 when present, is heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is heteroaryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is unsubstituted heteroaryl.
- Ar 1 when present, is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- aryls include, but are not limited to, phenyl, naphthyl, phenanthryl, and anthracenyl.
- Ar 1 when present, is aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is aryl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CO 2 R 20 , ⁇ OC(O)(C1-C4 alkyl), C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
- Ar 1 when present, is unsubstituted aryl.
- Ar 1 when present, is aryl or heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from hydrogen, ⁇ Br, ⁇ Cl, ⁇ F, ⁇ I, ⁇ OC(O)(CH 3 ), ⁇ OC(O)(CH 2 CH 3 ), ⁇ OC(O)(CH(CH 3 ) 2 ), ⁇ OC(O)(CH 2 CH 2 CH 3 ), ⁇ OC(O)(CH(CH 2 CH 3 )CH 3 ), ⁇ OC(O)(CH 2 CH 2 CH 3 ), ⁇ OC(O)(CH 2 CH 2 CH 3 ), methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, n-propenyl, isopropenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, –CH 2 CH 2 CH 2 CH
- Ar 1 when present, is aryl or heteroaryl substituted with 0, 1, or 2 groups independently selected from hydrogen, ⁇ Br, ⁇ Cl, ⁇ F, ⁇ I, ⁇ OC(O)(CH 3 ), ⁇ OC(O)(CH 2 CH 3 ), ⁇ OC(O)(CH(CH 3 ) 2 ), ⁇ OC(O)(CH 2 CH 2 CH 3 ), ⁇ OC(O)(CH(CH 2 CH 3 )CH 3 ), ⁇ OC(O)(CH 2 CH 2 CH 2 CH 3 ), methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, n-propenyl, isopropenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, – CH 2 CH 2 CH 2 F, –CH(CH 3 ) 2 Cl, –CH(CH 3 ) 2 Cl, –
- Ar 1 when present, is aryl or heteroaryl substituted with 0 or 1 group selected from hydrogen, ⁇ Br, ⁇ Cl, ⁇ F, ⁇ I, ⁇ OC(O)(CH 3 ), ⁇ OC(O)(CH 2 CH 3 ), ⁇ OC(O)(CH(CH 3 ) 2 ), ⁇ OC(O)(CH 2 CH 2 CH 3 ), ⁇ OC(O)(CH(CH 2 CH 3 )CH 3 ), ⁇ OC(O)(CH 2 CH 2 CH 2 CH 3 ), methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, n-propenyl, isopropenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, – CH 2 CH 2 CH 2 F, –CH(CH 3 ) 2 Cl, –CH(CH 3 ) 2 Cl,
- Ar 1 when present, is aryl or heteroaryl monosubstituted with a group selected from hydrogen, ⁇ Br, ⁇ Cl, ⁇ F, ⁇ I, ⁇ OC(O)(CH 3 ), ⁇ OC(O)(CH 2 CH 3 ), ⁇ OC(O)(CH(CH 3 ) 2 ), ⁇ OC(O)(CH 2 CH 2 CH 3 ), ⁇ OC(O)(CH(CH 2 CH 3 )CH 3 ), ⁇ OC(O)(CH 2 CH 2 CH 2 CH 3 ), methyl, ethyl, n-propyl, isopropyl, butyl, ethenyl, n-propenyl, isopropenyl, –CH 2 Cl, –CH 2 F, –CH 2 CH 2 Cl,–CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, – CH 2 CH 2 CH 2 F, –CH(CH 3 ) 2 Cl, —
- Ar 1 is selected from naphthyl, furanyl, benzofuranyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, quinolinyl, quinazolinyl, indazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, isoquinolinyl, and imidazopyridinyl.
- a compound can be present as: or a pharmaceutically acceptable salt thereof.
- a compound can be present as: or a pharmaceutically acceptable salt thereof.
- C. PHARMACEUTICAL COMPOSITIONS [00243]
- disclosed are pharmaceutical compositions comprising a disclosed compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- compositions comprising a therapeutically effective amount of a compound having a structure represented by a formula: , wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C1-C
- compositions comprising a therapeutically effective amount of a compound having a structure represented by a formula: , wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 al
- compositions comprising a therapeutically effective amount of a compound: , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration.
- the compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.
- a pharmaceutical composition can be formulated for local or systemic administration, intravenous, topical, or oral administration.
- the nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art.
- the pharmaceutical composition is sterile or sterilizable.
- the therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol.
- nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration.
- administration can be parenteral, intravenous, subcutaneous, or oral.
- a modulatory compound can be formulated in various ways, according to the corresponding route of administration.
- liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.
- the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants.
- the instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention.
- the compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
- the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- oral liquid preparations such as suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
- tablets can be coated by standard aqueous or nonaqueous techniques.
- a tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
- the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water.
- compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
- compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
- Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices.
- compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art.
- the suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
- the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
- other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
- Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof can also be prepared in powder or liquid concentrate form.
- an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.
- the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.
- the pharmaceutical composition is used to treat a disorder of uncontrolled cellular proliferation such as, for example, cancers including, but not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).
- cancers including, but not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial
- compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
- D. METHODS OF MAKING COMPOUNDS [00265] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein. [00266] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below.
- the disclosed compounds can be prepared by Routes I-IV, as described and exemplified below.
- the following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1.
- ROUTE I [00267]
- substituted TDZD analogs can be prepared as shown below. SCHEME 1A.
- Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
- compounds of type 1.6 and similar compounds can be prepared according to reaction Scheme 1B above.
- compounds of type 1.6 can be prepared by reacting an isothiocyanate, e.g., 1.4 as shown above, with a corresponding isocyanate, e.g., 1.5 as shown above.
- Appropriate isothiocyanates and appropriate isocyanates are commercially available or prepared by methods known to one skilled in the art. The reaction is carried out in the presence of an appropriate chloride source, e.g., sulfuryl chloride as shown above, and an appropriate solvent, e.g., tetrahydrofuran (THF), at an appropriate temperature, e.g., 0 °C, for an appropriate period of time, e.g., 30 minutes.
- an appropriate chloride source e.g., sulfuryl chloride as shown above
- an appropriate solvent e.g., tetrahydrofuran (THF)
- a protecting group can be used during the coupling reaction.
- an appropriate deprotecting agent e.g., trifluoracetic acid
- an appropriate solvent e.g., dichloromethane
- the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1 and 1.2) can be substituted in the reaction to provide 2,4-disubstituted thiadiazolidinone analogs similar to Formula 1.3 as shown in Scheme 1A above. 2.
- ROUTE II [00270]
- substituted TDZD analogs can be prepared as shown below.
- compounds of type 2.6 and similar compounds can be prepared according to reaction Scheme 2B above.
- compounds of type 2.6 can be prepared by a coupling reaction between an appropriate acid, e.g., 2-acetoxybenzoic acid 2.4 as shown above, and an appropriate amine, e.g., 2.5 as shown above.
- Appropriate acids and appropriate amines are commercially available or prepared by methods known to one skilled in the art.
- the reaction is carried out by converting the acid, e.g., 2.4, to its acid chloride using an appropriate chloride source, e.g., oxalyl chloride as shown above, in an appropriate solvent such as dichloromethane as shown above, for an appropriate time, e.g., 30 minutes.
- the acid chloride can then be coupled to an amine, e.g., 2.5, using an appropriate base, e.g., N,N-diisopropylethylamine (DIPEA), in an appropriate solvent, e.g., dichloromethane as shown above, for an appropriate time, e.g., one hour as shown above, to give the product, e.g., 2.6.
- DIPEA N,N-diisopropylethylamine
- compounds of type 3.6 and similar compounds can be prepared according to reaction Scheme 3B above.
- compounds of type 3.6 can be prepared by reacting a triazole, e.g., 3.4, with a corresponding alcohol or amine, e.g., 3.5.
- a triazole e.g., 3.4
- a corresponding alcohol or amine e.g., 3.5
- Appropriate triazoles, appropriate alcohols, and appropriate amines are commercially available or prepared by methods known to one skilled in the art.
- the coupling reaction can be carried out with a suitable base, e.g., N,N-diisopropylethylamine (DIPEA) as shown above, in an appropriate solvent, e.g., dichloromethane as shown above, for an appropriate time, e.g., one hour, to give the product, e.g., 3.6.
- DIPEA N,N-diisopropylethylamine
- dichloromethane e.g., dichloromethane
- the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1 and 3.2) can be substituted in the reaction to provide 2,4-disubstituted thiadiazolidinone analogs similar to Formula 3.3 as shown in Scheme 3A above. 4.
- substituted TDZD analogs can be prepared as shown below.
- Compounds are represented in generic form, with X selected from –NH ⁇ and –O ⁇ , and other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.
- compounds of type 4.10 and similar compounds can be prepared according to reaction Scheme 4B above.
- compounds of type 4.8 can be prepared by reacting an alcohol, e.g., 4.6 as shown above, with maleic anhydride 4.7 to give the intermediate, e.g., 4.8.
- Appropriate alcohols are commercially available or prepared by methods known to one skilled in the art.
- the reaction can be carried out in a suitable solvent, e.g., dichloromethane as shown above, in the presence of a suitable base, e.g., triethylamine as shown above, for an appropriate time, e.g., 48 hours.
- a suitable solvent e.g., dichloromethane as shown above
- a suitable base e.g., triethylamine as shown above
- Compounds of type 4.10 can be prepared by reacting the intermediate, e.g., 4.8, with a corresponding amine, e.g., 4.9, in the presence of a suitable activating agent, e.g., chloro ethylformate as shown above, and a suitable base, e.g., triethylamine, in a suitable solvent, e.g., dichloromethane, at a suitable temperature, e.g., 0 °C.
- a suitable activating agent e.g., chloro ethylformate as shown above
- a suitable base e.g., triethylamine
- a suitable solvent e.g., dichloromethane
- the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 4.1, 4.2, 4.3, and 4.4) can be substituted in the reaction to provide 2,4-disubstituted thiadiazolidinone analogs similar to Formula 4.5 as shown in Scheme 4A above.
- E. TREATING DISORDERS OF UNCONTROLLED CELLULAR PROLIFERATION IN A SUBJECT [00279]
- methods of treating a disorder of uncontrolled cellular proliferation in a subject comprising the step of administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
- a disorder of uncontrolled cellular proliferation in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)
- a disorder of uncontrolled cellular proliferation in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl
- a disorder of uncontrolled cellular proliferation in a subject comprising administering to the subject an effective amount of a compound selected from: or a pharmaceutically acceptable salt thereof.
- methods for treating a disorder of uncontrolled cellular proliferation in a subject comprising administering to the subject an effective amount of a compound: or a pharmaceutically acceptable salt thereof.
- the effective amount is a therapeutically effective amount.
- the effective amount is a prophylactically effective amount.
- the subject is a mammal. In a still further aspect, the mammal is a human.
- the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.
- the method further comprises the step of identifying a subject in need of treatment of the disorder.
- the disorder is a cancer.
- cancers include, but are not limited to, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, and plasma cell neoplasm (myeloma).
- the cancer is a hematological cancer.
- the hematological cancer is selected from leukemia, lymphoma, and multiple myeloma.
- the cancer is a solid tumor.
- the solid tumor is selected from lung cancer, liver cancer, pancreatic cancer, a central nervous system cancer, breast cancer, ovarian cancer, colon cancer, renal cancer, melanoma, prostate cancer, and head and neck cancer.
- a neurodegenerative disorder in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(
- a neurodegenerative disorder in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(
- disclosed are methods for treating a neurodegenerative disorder in a subject comprising administering to the subject an effective amount of a compound selected from: or a pharmaceutically acceptable salt thereof.
- methods for treating a neurological disorder in a subject comprising administering to the subject an effective amount of a compound selected from:
- the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
- the subject is a mammal. In a still further aspect, the mammal is a human.
- the subject has been diagnosed with a need for treatment of the neurological disorder prior to the administering step.
- the method further comprises the step of identifying a subject in need of treatment of the neurological disorder.
- the neurological disorder is associated with age.
- the neurological disorder is selected from sarcopenia, supranuclear palsy, Alzheimer’s disease, and dementia.
- the compounds and pharmaceutical compositions of the invention are useful in treating or controlling neurodegenerative diseases and disorders of uncontrolled cellular proliferation such as, for example, cancer.
- Examples of neurodegenerative diseases for which compounds and compositions can be useful in treating include, but are not limited to, sarcopenia, supranuclear palsy, Alzheimer’s disease, dementia.
- disorders of uncontrolled cellular proliferation for which the compounds and compositions can be useful in treating include, but are not limited to, cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).
- cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, end
- the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian.
- a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian.
- the subject can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
- the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
- the subject is preferably a mammal, such as a human.
- the subject Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a disorder of uncontrolled cellular proliferation, such as cancer.
- the compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
- a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
- a preparation can also be administered prophylactically; that is, administered for prevention of a disorder of uncontrolled cellular proliferation, such as cancer.
- the therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded.
- the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion.
- Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose.
- the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1. USE OF COMPOUNDS [00308]
- the invention relates to the use of a disclosed compound or a product of a disclosed method.
- a use relates to the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a subject.
- a use relates to the manufacture of a medicament for the treatment of a neurodegenerative disease in a subject.
- the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
- the compound used is a product of a disclosed method of making.
- the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.
- the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.
- the use relates to a treatment of a disorder of uncontrolled cellular proliferation in a subject.
- the use is characterized in that the subject is a human.
- the use is characterized in that the disorder of uncontrolled cellular proliferation is a cancer.
- the use relates to a treatment of a neurodegenerative disease in a subject.
- the use is characterized in that the subject is a human.
- the use is characterized in that the neurodegenerative disease is selected from sarcopenia, supranuclear palsy, Alzheimer’s disease, and dementia.
- the use relates to the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a subject.
- the use relates to the manufacture of a medicament for the treatment of a neurodegenerative disease in a subject.
- the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits.
- the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.
- the disorder of uncontrolled cellular proliferation is a cancer.
- the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a neurodegenerative disease in a mammal.
- the neurodegenerative disease is selected from sarcopenia, supranuclear palsy, Alzheimer’s disease, and dementia.
- the invention relates to a method for the manufacture of a medicament for treating a disorder of uncontrolled cellular proliferation in a subject having the disorder, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
- the invention relates to a method for the manufacture of a medicament for treating a neurodegenerative disease in a subject having the disorder, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
- the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of a disorder of uncontrolled cellular proliferation.
- the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame.
- the total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 0.05 mg/kg and about 100 mg/kg of body weight for mice, and more preferably between 0.05 mg/kg and about 50 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose.
- This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
- the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
- the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.
- kits comprising an effective amount of a disclosed compound, and one or more of: (a) at least one agent associated with the treatment of a disorder of uncontrolled cellular proliferation; (b) at least one agent associated with the treatment of a neurological disorder; (c) instructions for administering the compound in connection with treating a disorder of uncontrolled cellular proliferation; (d) instructions for administering the compound in connection with treating a neurological disorder; (e) instructions for treating a disorder of uncontrolled cellular proliferation; and (f) instructions for treating a neurological disorder.
- kits comprising an effective amount of a compound having a structure represented by a formula: , wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)
- kits comprising an effective amount of a compound having a structure represented by a formula: , wherein m is 0, 1, 2, or 3; wherein R 1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C1-C10 cyanoalkyl, C1-C10 nitroalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxy, C1- C10 alkenoxy, C1-C10 thioalkyl, C1-C10 alkylthiol, C1-C10 alkylamino, (C1-C10)(C1-C10) dialkylamino, C1-C10 aminoalkyl, ⁇ (C1-C10 alkyl) ⁇ O ⁇ (C1-C10 alkyl), ⁇ (C1-C10 alkyl)C(O)R 10 , ⁇ (C1-C10 alkyl)
- kits comprising an effective amount of a compound selected from: or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one agent associated with the treatment of a disorder of uncontrolled cellular proliferation; (b) at least one agent associated with the treatment of a neurological disorder; (c) instructions for administering the compound in connection with treating a disorder of uncontrolled cellular proliferation; (d) instructions for administering the compound in connection with treating a neurological disorder; (e) instructions for treating a disorder of uncontrolled cellular proliferation; and (f) instructions for treating a neurological disorder.
- the agent associated with the treatment of a disorder of uncontrolled cellular proliferation is a chemotherapeutic agent.
- the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and an mTor inhibitor agent.
- the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.
- the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.
- the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.
- the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.
- the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
- the agent associated with the treatment of a neurological disorder is selected from a cholinesterase inhibitor, an antidepressant, memantine, rilutek, radicava, levodopa, carbidopa, a dopamine agonist, a MAO-B inhibitor, a catechol-O- methyltransferase inhibitor, an anticholinergic, spinraza, tetrabenazine, an antipsychotic agent, levetiracetam, clonazepam, an antipsychotic agent, a mood-stabilizing agent, and amantadine.
- the disorder of uncontrolled cellular proliferation is a cancer.
- the neurological disorder is selected from sarcopenia, supranuclear palsy, Alzheimer’s disease, and dementia.
- the compound and the agent are co-packaged.
- the compound and the agent are administered sequentially.
- the compound and the agent are administered simultaneously.
- TDZD-aspirin analogs were synthesized by dissolving 2- acetoxybenzoic acid in dichloromethane and converting it to its acid chloride by reaction with oxalyl chloride followed by addition of a few drops of dimethyl formamide.
- MMB was reacted with maleic anhydride in the presence of triethylamine in dichloromethane (DCM) as a solvent at ambient temperature for 48 h to form MMB-carboxylic acid.
- DCM dichloromethane
- the obtained MMB-carboxylic acid intermediate was further reacted with ethyl chloroformate in the presence of triethylamine in dry tetrahydrofuran (THF), followed by reaction with TDZD amine to obtain MMB-TDZD amide and ester conjugated derivatives (Structure VII, Scheme 6).
- MMB was reacted with fumaric acid in the presence of N- (3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), triethylamine in dry dimethylformamide at 0 °C to RT over 12 h to afford MMB- fumarate.
- EDC N- (3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
- HOBt 1-hydroxybenzotriazole
- MMB-fumarate intermediate was further reacted with ethyl chloroformate in the presence of triethylamine in dry THF, followed by reaction with amino TDZD or hydroxyl TDZD to afford MMB-TDZD fumaric acid amide or ester conjugates (Structure VIII).
- TDZD analogues in a general procedure for the synthesis of novel TDZD analogues, the use of various solvents such as, for example, chloroform, dichloromethane (DCM), diethyl ether, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, and mixtures thereof, is envisioned.
- the temperature for the formation of TDZD compounds can range from about 0 °C to reflux temperatures, but the optimal temperature range is 0 to 5 °C.
- SYNTHESIS AND ANALYTICAL DATA i.
- reaction mixture was stirred for 1h, after completion of reaction (monitored by TLC), added water and the aqueous mixture was extracted with dichloromethane. The separated organic layer was washed with water, followed by brine solution, dried over anhydrous Na 2 SO 4 and concentrated to afford the crude O-Boc- protected BSK-314.
- This crude product was purified by column chromatography (silica gel, 2% methanol in dichloromethane) to afford pure O-Boc-protected BSK-314, as a white solid.
- N-Boc-protected BSK-269 was treated with trifluoroacetic acid (2eq) in dichloromethane and stirred for 6 h. Then, Saturated NaHCO 3 solution was added to the reaction mixture and extracted with dichloromethane. The separated organic layer was washed with water, followed by brine solution and dried over anhydrous Na 2 SO 4 , concentrated to afford pure BSK-269 analog as white solid.
- FIG.15 Data from a screen conducted using SY5Y-APP are shown in FIG.15.
- FIG. 16 Alignment and molecular descriptors achieved using Maestro are shown in FIG. 16.
- FIG. 17. Data from a screen conducted on 16 compounds in SY5Y-APP are shown in FIG. 17. b.
- TDZD-conjugated drugs were evaluated for their ability to reduce accumulation of protein aggregates, and for protection against aggregation- associated end-points in the following model systems: (i.) SH-SY5Y-APPSw, a neuroblastoma cell line expressing the Swedish mutation of Amyloid Precursor Protein (APP Sw ), and thus predisposed to form ⁇ -amyloid deposits; (ii.) C.
- elegans strain CL4176 a model of Alzheimer- like amyloidopathy that can be induced to express human A ⁇ 1–42 in muscle, or may express it at a lower level without induction;
- C. elegans strain AM141 a model of Huntington-like polyglutamine aggregation that constitutively expresses Q40::YFP (a tract of 40 glutamines fused in-frame to yellow fluorescent protein) in muscle cells and forms aggregates progressively with adult aging.
- the TDZD analog PNR-962 (a putative GSK-3 inhibitor) and other related compounds (not shown) were protective in all aggregation assays.
- TDZD analogues were tested on the human neuroblastoma cell line SH-SY5Y-APPSw, a model of Alzheimer-like amyloid aggregation expressing the “Sw” mutant form of Amyloid Precursor Protein, APP. These drugs all produced significant reductions in amyloid-like aggregates, by 30 ⁇ 50% as quantified by thioflavin-T staining intensity (data for PNR-962 are shown in FIG.4). Modified TDZD-8 analogues PNR-962 and BSK-179 are more anti-aggregative than TDZD-8, lowering total amyloid-staining intensity by a further 14% (data not shown).
- BSK-179 comprises an acetyl donor (similar to aspirin), coupled to PNR-962. It reduced the total intensity of Q40::YFP aggregates by >2-fold, a substantially greater protection than afforded by PNR-962 or aspirin alone (FIG.7).
- acetyl donor similar to aspirin
- PNR-962 and BSK-179 extended the lifespan of wild-type nematodes to an identical degree, increasing the mean by roughly 25–30% (P ⁇ 0.001; FIG.8).
- a TDZD-ibuprofen analog (BSK-137), a drug combining the GSK-3 inhibitor with Ibuprofen, was synthesized and its effect on protein aggregation was tested in neuronal cells.
- the combination drug BSK-137 reduced aggregate intensity by 34% as evidenced by reduced Thioflavin –T staining (FIG.9).
- the small-molecule library was modeled, the ligands prepared, structures superimposed by a common ring or side-chain of interest (TDZD ring), and molecular spreadsheets were subsequently generated in Maestro covering over 400 molecular descriptors.
- the molecular descriptors generated included 1-dimensional (e.g., atom count, molecular weight, and number of bonds), 2-dimensional (e.g., topological, structural, functional-group count), 3-dimensional (e.g.. electronic, spatial, and geometric indices) and 4-dimensional (4D, i.e., time-dependent) features.
- a robust QSAR pipeline was designed, tested, and validated using other endpoints like log(IC50) of anti-aggregative activity, and 7 highly optimized machine learning algorithms were employed, namely, k-nearest neighbors (KNN), neural network (NN), partial least squares (PLS), support vector machine (SVM), bagging (B), random forest (RF), and decision tree (DT), for predictive QSAR modeling for the TDZD family of small molecules.
- KNN k-nearest neighbors
- N neural network
- PLS partial least squares
- SVM support vector machine
- B bagging
- RF random forest
- DT decision tree
- a virtual screening for the entire TDZD library was performed using the most predictive well-tuned algorithm followed by ranking and testing for the activity to assess the correlation (agreement) between predicted vs. observed activity. Subsequently, the relative importance of the major molecular descriptors useful in predicting aggregation inhibition activity of TDZD analogs in the small-molecule library will be estimated.
- the synthesis of the most active candidate compounds in the library to treat AD and associated neurodegenerative diseases can be guided.
- the compounds predicted to be most active will be synthesized and then characterized in human cell-culture and nematode models of AD, for aggregation inhibition, age-progressive paralysis, and life span studies, among others. d.
- MMB triazole analogs are potent NF- ⁇ B inhibitors and anti-cancer agents against both hematological and solid tumor cells.
- Unbiased docking of ligands to the allosteric pocket in the GSK3 ⁇ inactive conformation was performed using Autodock-Vina with Raccoon interface via a Linux- based server.
- the grid box was created using the Receptor Grid Generator Wizard in Maestro. Docking computations were performed in standard precision mode, which ensures flexible ligand sampling. Visualization and analysis of results were all carried out in Maestro Viewer and Discovery Studio Visualizer.
- the prepared ligand-protein molecular complexes (PNR962-GSK3 ⁇ , and TDZD-8-GSK3 ⁇ ) were each enclosed in an orthorhombic box, ensuring that all edges of the box are at least 10- ⁇ from the protein.
- Solvation and neutralization of the boxed protein were accomplished with Simple Point Charge (SPC) water and Na + , Cl- counter- ions, respectively. NaCl was added at 0.15 M to ensure the appropriate physiological salt concentration.
- the Simulation Interaction Diagram Generator module in Desmond-Maestro was used to view and analyze the resulting simulation trajectories for the protein-ligand simulated complex. g.
- RNA samples were evaluated for anti-leukemic activity against the MV4-11 cell line (myelomonocytic leukemia), utilizing PTL and TDZD-8 as reference positive- control drugs in all assays.
- the results from the MV4-11 cell assay indicated that the MMB- TDZD analogs (BSK-140 to BSK-271) were cytotoxic to MV4-11 cells with equal or greater potency to that of parthenolide (PTL) or TDZD-8.
- PTL parthenolide
- BSK-259 and BSK- 230 were the most potent antileukemic agents examined, with LD50 values of 10 nM and 20 nM, respectively.
- BSK-259 is 273-fold more cytotoxic than PTL and 329-fold more cytotoxic than TDZD-8.
- Other compounds of interest were BSK-2-68, BSK-271, BSK-218 and BSK-197, which exhibited LD50 values 130 nM, 680 nM, 760 nM and 980 nM respectively. See Table 2, which shows the LD50 ( ⁇ M) values of MMB-TDZD analogs against cultured MV-411 cells after 24-h. T ABLE 2.
- the synthesized Ibuprofen-TDZD combination drugs were evaluated for anti- leukemic activity against MV4-11 cell lines by utilizing TDZD-8 as a positive control in all assays.
- the results from the MV4-11 cell assay indicated that the Ibuprofen-TDZD analogs (BSK-137 to BSK-270) exhibited cytotoxic potency equal or greater than 2.3-fold that of TDZD- 8.
- Compounds BSK-260 and BSK-236 were the most potent antileukemic agents examined with LD 50 values of 1.42 ⁇ M and 1.75 ⁇ M, respectively.
- TDZD-aspirin TDZD-ibuprofen
- TDZD-MMB analogs novel combination drugs
- the TDZD-ibuprofen analog (BSK-137), reduced aggregate intensity by 34%.
- Three of the hybrid drugs (BSK-259, BSK-226 and BSK-230) exhibited the most potent growth inhibition, with GI50 values in the range 280-900 nM against human leukemia cell lines.
- Compound BSK-226 also had GI 50 values 530 nM and 560 nM against cell lines NCI-H522 (non-small-cell lung cancer) and HCT-116 (colon cancer), respectively.
- Compound BSK-259 was the most potent compound against the MV4-11 cell line with an LD50 value (50% lethality) of 10 nM.
- the assay was done in three replicates at three doses (0.01, 0.1, and 1 ⁇ M) of each inhibitor (TDZD8, PNR962) in a 96-well plate, using 1% DMSO (final solvent concentration) as the drug-free control.
- the kinase assay reaction was incubated for 45 minutes at 30 0 C and Kinase-Glo Max Assay (Promega) was then added and incubated for 15 minutes at room temperature.
- a negative control contained all the reagents except the test inhibitors and GSK3 ⁇ enzyme and positive control contained all reagents except the test inhibitor.
- SpectraMax M3 (Molecular Devices, LLC) was used as a microplate reader.
- TDZD-aspirin analogs were synthesized by dissolving 2-acetoxybenzoic acid in dichloromethane and converting it to its acid chloride by reaction with oxalyl chloride followed by addition of a few drops of dimethyl formamide.
- TDZD analogues Prior to assay, cells were grown 48 h in the presence of TDZD analogues at 4 doses (0.001, 0.01, 0.1, and 1 ⁇ M) dissolved in DMSO (diluted in culture medium to 0.02% final DMSO concentration) or the same final concentration of DMSO for control cells.
- Human neuroblastoma cells were treated with PNR962, either simultaneous with sAPP ⁇ or beginning 1 h prior to sAPP ⁇ addition (pre-treatment) in order to ascertain the protective benefits of PNR962 on protein aggregation in human neuroblastoma cell lines.
- ELEGANS STRAINS [00408] All nematode strains used in this research were obtained from the Caenorhabditis Genetics Center (CGC; Minneapolis, MN, USA): wild-type Bristol-N2 [DRM stock]; CL4176 [smg-1 ts ; myo-3p::A ⁇ 1–42 ::let-8513′-UTR; rol-6(su1006)] which expresses human A ⁇ 1–42 in body wall muscle and AM141 that expresses polyglutamine [Q40] fused in ⁇ frame to YFP [Q40::YFP] in muscle cells.
- CGC Caenorhabditis Genetics Center
- elegans strains were maintained at 20 °C on 2% (w/v) agar plates in nematode growth medium (NGM), seeded in the center with E. coli strain OP50. h. EFFECTS OF NOVEL TDZD ANALOGS ON PROTEIN AGGREGATION IN C. ELEGANS STRAIN AM141 [00409] Fresh agar plates supporting bacterial lawns, which serve as food for C. elegans, were prepared at least 1 day ahead of use. C. elegans AM141 (forming Q40::YFP aggregates in muscle, progressively in early adulthood) were placed on these 100-mm plates.
- Day-4 adult worms were lysed with alkaline hypochlorite solution to obtain eggs from worms, a procedure that permits synchronization of worms in a cohort.
- Eggs were placed on plates spotted with different concentrations of TDZD analogues after allowing the compounds to be evenly distributed on the plates ( ⁇ 1 hour after adding drugs to plates).
- Vehicle-only (DMSO) controls are included in each experiment, as a baseline for drug effects in experimental groups.
- Young-adult AM141 (day-3 adults) were transferred on alternate days onto fresh plates that contained the same doses of compounds, with fresh E. coli to prevent starvation of worms.
- Worms were maintained at 20 °C with ample E. coli (OP50) bacteria, and lysed at day 3.5 post-hatch (adult day 1), releasing unlaid eggs to generate a synchronized cohort.
- Eggs were plated on 100-mm Petri dishes containing NGM-agar seeded in a central area with OP50 bacteria plus drug or vehicle (to a final concentration of 0.02% v/v DMSO).
- Worms were either upshifted to 25.5 °C at the L3-L4 transition to induce expression of the human A ⁇ 1-42 transgene and assayed after a further 48 hr., or were aged without induction and assayed at a series of later times.
- both PNR-886 and PNR-962 have greatly improved binding affinity for GSK3 ⁇ .
- the Gibbs Free Energy of binding ( ⁇ G binding) calculated by the MM/GBSA method for PNR886 and PNR962 predicts that both drugs have high binding affinity for GSK3 ⁇ in the inactive conformation (FIG.18G). Snapshots were taken from 0.5- ⁇ s simulations of full-length GSK3 ⁇ bound to TDZD-8 and its analogs PNR886 and PNR962, at 0-ns, 100-ns and 200-ns (FIG.19A-I).
- Root Mean Square Deviation (RMSD) of protein– ligand complexes, during 200-ns simulations of GSK3 ⁇ binding to TDZD-8, PNR962, and PNR886, predict stable binding of these compounds to the allosteric hydrophobic pocket of the inactive GSK3 ⁇ conformation (FIG.19J-L).
- Schrödinger Maestro 11.4 https://www.schrodinger.com/ was used to depict the docked molecular structures.
- b. ANALYSIS OF DRUG DOCKING WITH GSK-3 ⁇ [00414] Drug docking with GSK-3 ⁇ (by SeeSAR) was analyzed to identify GSK3 ⁇ inhibitors effective in the nM range.
- Hyperphosphorylated tau is readily sequestered into aggregates and generates intracellular neurofibrillary tangles (“tau tangles”).
- tau tangles intracellular neurofibrillary tangles
- GSK3 ⁇ was shown to phosphorylate tau at serine 202 and threonine 205, initiating hyperphosphorylation of tau at other sites.
- the top drugs were tested for impact on tau hyperphosphorylation in rat cortical cells (FIG.23).
- MOUSE TESTING [00418] Mice are now being treated with PNR962, one of the lead compounds in this screen, for its efficacy in reducing aggregation and improving cognition (assessed by novel- object recognition and Morris water-maze tests).
- BRI-A ⁇ transgenic mice a model of age-dependent, cerebral amyloid deposition, are used.
- NEURONAL CULTURES [00419] Primary cultures were established from cerebral cortex of E18 rats; under serum-free conditions (Neurobasal/B27) these cultures contain ⁇ 85% neurons, with the remainder comprising astrocytes ( ⁇ 12% and microglia ⁇ 3%). At the 8 th population doubling, triplicate cultures were exposed to the test compounds at the indicated concentrations; a separate triplicate was exposed to vehicle (0.5% DMSO final concentration). After 24 h, cultures were washed once with ice-cold PBS and then scraped in RIPA buffer containing inhibitors of proteases and phosphatases.
- Lysates were centrifuged at 14,000g at 4 °C for 7 min. Supernatants were removed and stored at -80 °C after removal of small aliquots for determination of protein concentration by BCA. Samples equilibrated for total protein were analyzed by WesTM capillary-gel immunodetection (ProteinSimple) using the AT8 clone of anti-phosphoTau (Invitrogen MN1020) or total Tau (ABclonal A0002). Detected antigen was calculated by peak area (automated peak fit), and values are reported as AT8 normalized to total Tau. 5.
- Arylimino-1,2,4- thiadiazolidinones A new family of potassium channel openers. Bioorganic & Medicinal Chemistry.1997;5(7): 1275-1283. [00429] Martinez A., Alonso D., Castro A., et al. Synthesis and potential muscarinic receptor binding and antioxidant properties of 3-(thiadiazolyl)pyridine 1-oxide compounds. Arch Pharm (Weinheim). 1999;332(6): 191-194. [00430] Dominguez J.M., Fuertes A., Orozco L., del Monte-Millan M., Delgado E., Medina M.
- the NF (Nuclear factor)-kappaB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1- dependent apoptosis in human acute myeloid leukaemia cells.
- Deschler B. Lubbert M.
- Acute myeloid leukemia epidemiology and etiology. Cancer.2006;107(9): 2099-2107.
- Estey E. Döhner H. Acute myeloid leukaemia. The Lancet.2006;368(9550): 1894-1907.
- Löwenberg B. Suciu S., Archimbaud E., et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report.
- a first aspect of the present disclosure provides design and synthesis of the compounds of given general structure (Structure I), and evaluation of the compounds of general structure (Structure I), as inhibitors of protein aggregation, which are expected to delay, prevent, or reverse age-associated diseases including but not limited to sarcopenia; Alzheimer’s disease and other dementias; hematologic cancers such as leukemia, lymphoma and multiple myeloma; and solid tumors such as lung cancer, liver cancer, pancreatic cancer, CNS cancers, breast cancer, ovarian cancer, colon cancer, renal cancer, melanoma, prostate cancer and head and neck cancers.
- the second aspect of the present disclosure is formulation of novel TDZD analogues utilizing pharmaceutically acceptable salts, or by employing nanoparticle drug- delivery formulations.
- the compound comprising structure-I may be a free form or a salt.
- the compound salt is preferably a pharmaceutically acceptable salt.
- Pharmaceutically acceptable salts may include, without limitation, hydrochloride, hydrobromide, phosphate, sulfate, methane-sulfonate, acetate, formate, tartaric acid, bitartrate, stearate, phthalate, hydroiodide, lactate, monohydrate, mucate, nitrate, phosphate, salicylate, phenylpropionate, isobutyrate, hypophosphite, maleic acid, malic acid, citrate, isocitrate, succinate, lactate, gluconate, glucuronate, pyruvate, oxalate, fumarate, propionate, aspartate, glutamate, benzoate, terephthalate, and the like.
- the pharmaceutical acceptable salt includes an alkaline or alkaline earth metal ion salt.
- sodium, potassium or other pharma-ceutically acceptable inorganic salts are used.
- the fourth aspect of the present disclosure provides a composition of the general structures that may be chosen from (E) or (Z)-isomers, or R- and S- isomers for chiral molecules.
- the fifth aspect of the present disclosure is route of administration (drug delivery) of all the aforementioned novel TDZD analogues, which may include (without limitation) oral, intravenous, intraperitoneal, intramuscular, intrathecal, intranasal, transdermal, subdermal (depot), inhalation, or buccal.
- the sixth aspect of the present disclosure is that all the aforementioned novel TDZD analogues may be polymorphic in form, including amorphous or crystalline composition, or any other physical state in formulations that may enhance the pharmacokinetic properties of the molecule.
- the salt forms may be amorphous or in various polymeric forms including hydrates, or solvates with alcohols or other solvents.
- Pharmaceutical Compositions The disclosure also provides a pharmaceutical composition comprising the compound comprising structure I and at least one pharmaceutically acceptable excipient. One or more of the compounds described in this disclosure may be combined with at least one pharmaceutically acceptable excipient.
- a pharmaceutical composition of the disclosure comprises at least one pharmaceutically acceptable excipient.
- Non-limiting examples of suitable excipients may include diluents, binders, fillers, buffering agents, pH modifying agents, disintegrants, dispersing agents, stabilizers, preservatives, and coloring agents.
- the amount and types of excipients may be selected according to known principles of pharmaceutical science.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062976604P | 2020-02-14 | 2020-02-14 | |
PCT/US2021/017970 WO2021163572A1 (en) | 2020-02-14 | 2021-02-12 | Novel tdzd analogs as agents that delay, prevent, or reverse age-associated diseases; and as anti-cancer and antileukemic agents |
Publications (2)
Publication Number | Publication Date |
---|---|
EP4103692A1 true EP4103692A1 (en) | 2022-12-21 |
EP4103692A4 EP4103692A4 (en) | 2024-05-29 |
Family
ID=77292954
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21754449.3A Pending EP4103692A4 (en) | 2020-02-14 | 2021-02-12 | Novel tdzd analogs as agents that delay, prevent, or reverse age-associated diseases; and as anti-cancer and antileukemic agents |
Country Status (3)
Country | Link |
---|---|
US (1) | US20230125667A1 (en) |
EP (1) | EP4103692A4 (en) |
WO (1) | WO2021163572A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116675653A (en) * | 2022-07-22 | 2023-09-01 | 中国药科大学 | Aminoalkyl substituted 1,2, 4-thiadiazolidine-3, 5-dione compound, preparation method and application thereof |
CN117986202B (en) * | 2024-04-03 | 2024-06-14 | 中国药科大学 | 1,2, 4-Thiadiazolidine-3, 5-dione compound with PTPN2 inhibitory activity, and preparation method and application thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005024755A2 (en) * | 2002-12-31 | 2005-03-17 | Deciphera Pharmaceuticals, Llc. | Medicaments for the treatment of neurodegenerative disorders or diabetes |
-
2021
- 2021-02-12 US US17/799,638 patent/US20230125667A1/en active Pending
- 2021-02-12 EP EP21754449.3A patent/EP4103692A4/en active Pending
- 2021-02-12 WO PCT/US2021/017970 patent/WO2021163572A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
EP4103692A4 (en) | 2024-05-29 |
WO2021163572A1 (en) | 2021-08-19 |
US20230125667A1 (en) | 2023-04-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI738753B (en) | Heterocyclic compound | |
JP6147727B2 (en) | Substituted N- (3- (pyrimidin-4-yl) phenyl) acrylamide analogs as tyrosine receptor kinase BTK inhibitors | |
CA2986930C (en) | Chemical modulators of signaling pathways and therapeutic use | |
CN102822171B (en) | As the benzo naphthyridines amine of autotaxin inhibitors | |
EP3191484B1 (en) | Pyrazolopyridine derivatives and their use in therapy | |
ES2798289T3 (en) | Heterocyclic compounds and methods for their use | |
JP2014509660A (en) | Substituted 3- (1H-benzo {d} imidazol-2-yl) -1H-indazole analogs as inhibitors of PDK1 kinase | |
AU2020401223A1 (en) | Compositions and methods for substituted 7-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine analogs as inhibitors of KRAS | |
JP2015535851A (en) | Substituted N- (3- (pyrimidin-4-yl) phenyl) acrylamide analogs that are tyrosine receptor kinase BTK inhibitors | |
WO2021163572A1 (en) | Novel tdzd analogs as agents that delay, prevent, or reverse age-associated diseases; and as anti-cancer and antileukemic agents | |
US10501466B2 (en) | WDR5 inhibitors and modulators | |
CA3182276A1 (en) | Inhibitors of nek7 kinase | |
WO2021236491A1 (en) | Benzoylhydrazide-derived hdac degraders as therapeutics for treating cancer and other human diseases | |
CN116075513A (en) | Inhibitors of NEK7 kinase | |
WO2023133221A2 (en) | Smarca2/4 inhibition as a strategy to treat tumors that harbor aberrant baf assemblies | |
ES2391371T3 (en) | 2-Trifluoromethylnicotinamide derivatives as agents to increase HDL-cholesterol | |
WO2019006322A1 (en) | Heterochromatin gene repression inhibitors | |
US11787768B2 (en) | Tetrahydroquinoline-based bromodomain inhibitors | |
EP3364976A1 (en) | Piperazinyl norbenzomorphan compounds and methods for using the same | |
CA3127990A1 (en) | Pipecolic esters for inhibition of the proteasome | |
WO2023274280A1 (en) | Crystal form of biphenyl derivative inhibitor and preparation method therefor | |
WO2023096822A1 (en) | Substituted 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide analogs as modulators of gspt1 and/or ikzf1 protein | |
WO2023081224A1 (en) | Substituted n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)methyl)benzamide analogs as modulators of cereblon protein | |
WO2023096995A1 (en) | Compositions and methods comprising substituted n-(2-chloro-6-methylphenyl)-2-((6-(6-membered heterocycloalkyl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide analogues | |
WO2023004138A1 (en) | Agonists of tyro3 as protection against podocyte injury in kidney glomerular disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20220914 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C12N 5/0775 20100101ALI20240205BHEP Ipc: C12N 5/077 20100101ALI20240205BHEP Ipc: C12N 5/071 20100101AFI20240205BHEP |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20240430 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C12N 5/0775 20100101ALI20240424BHEP Ipc: C12N 5/077 20100101ALI20240424BHEP Ipc: C12N 5/071 20100101AFI20240424BHEP |